Sacubitril/valsartan does not reduce NT-proBNP versus valsartan alone in HFrEF

Sacubitril/valsartan was not superior to valsartan at lowering N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients with heart failure and reduced ejection fractions (HFrEF) in the phase 4 LIFE trial [1]. It also did not improve clinical outcomes or reduce the risk of death in these patients when compared with valsartan alone. There was a statistically significant higher risk of hyperkalaemia associated with sacubitril/valsartan.

Sacubitril/valsartan is a first-in-class angiotensin receptor neprilysin inhibitor that demonstrated superior morbidity and mortality outcomes in patients with chronic HFrEF when compared with enalapril in the PARADIGM-HF trial [2]. However, very few (<1%) of the patients included in the PARADIGM-HF trial had advanced heart failure (defined as New York Heart Association [NYHA] class 4), and so evidence was lacking on the safety and efficacy of sacubitril/valsartan in this group of patients.

The LIFE trial (NCT02816736) was a phase 4, prospective, multicentre, double-blinded, double-dummy, active comparator trial that evaluated the efficacy of sacubitril/valsartan compared with valsartan alone at lowering NT-proBNP levels in patients with advanced HFrEF (NYHA class 4), following a 24-week intervention period. The researchers chose NT-proBNP level as the main outcome measure because it reflects haemodynamic and clinical status.

Prof. Douglas Mann (Washington School of Medicine, MO, USA) noted that the LIFE trial was impacted by the COVID-19 pandemic. They had originally planned to recruit 400 patients but were forced to suspend enrolment on 23 March 2020 due to the pandemic. As a result, their analysis was limited to 335 participants, 167 of whom were randomised to the sacubitril/valsartan arm, and the remaining 168 to the valsartan alone arm. The primary endpoint was the area under the curve (AUC) for the proportional change in NT-proBNP levels from baseline through 24 weeks. Neither of the groups decreased their median NT-proBNP levels to below baseline levels during the treatment period (see Figure).

Figure: Primary endpoint for the LIFE trial, AUC for the proportional change in the ratio of NT-proBNP levels to baseline [1]



AUC, area under the curve; NT-proBNP, pro-B-type natriuretic peptide.

Secondary endpoints included tolerability and an efficacy composite of the number of days that participants were:

• alive and not in hospital;
• neither listed for nor undergoing transplant;
• not implanted with a left ventricular device;
• not on inotropic therapy for ≥7 days; and
• not hospitalised twice for HF.

No differences in secondary endpoints between the groups were seen, except for a small but statistically significant increase in non-life-threatening hyperkalaemia in the sacubitril/valsartan arm (17% vs 9%; P=0.035).

The results do not demonstrate the superiority of sacubitril/valsartan over valsartan alone in lowering NT-proBNP levels in patients with advanced HFrEF.

1. 
   
   1. Mann DL. Sacubitril/valsartan in patients with advanced heart failure with reduced ejection fraction (LIFE trial). ACC 2021 Scientific Session, 15–17 May.
   2. McMurray JJV, et al. New Eng. J. Med 2014;371:993–1004.

 

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Posted on 9 July 202129 July 2021