Sacubitril/valsartan reduces natriuretic peptides in HF patients with ejection fraction >40%

Therapy with sacubitril/valsartan led to a significantly reduced NT-proBNP compared with valsartan alone; this was the most important result of the PARAGLIDE-HF trial. Even though beneficial effects were seen in several secondary endpoints, increased symptomatic hypotension also resulted from the therapy.

Several society guidelines recommend the consideration of sacubitril/valsartan to reduce hospitalisations in heart failure (HF) patients. A post-hoc analysis of PARAGON-HF (NCT01920711), which excluded patients with decompensated heart failure, suggested a larger benefit with sacubitril/valsartan in those recently hospitalised [1]. However, it remains unknown whether initiation of sacubitril/valsartan is safe and effective in patients with ejection fraction (EF) >40% stabilised after a worsening HF event. To evaluate this, the current phase 3 PARAGLIDE-HF study (NCT03988634) analysed 466 patients with HF with or without preserved EF (EF>40%) [2,3].

All participants had a recent worsening HF event and were enrolled in-hospital or within 30 days of HF hospitalisation. The average age was 70 years, 52% were women, and 22% were Black. They were randomised to treatment with sacubitril/valsartan (n=233) or valsartan alone (n=233). The primary endpoint was the time-averaged proportional change in NT-proBNP levels from baseline to weeks 4 and 8. Prof. Robert Mentz (Duke University Medical Center, NC, USA) presented the results.

The trial met its primary endpoint. A 15% greater reduction was seen in the NT-proBNP concentrations with sacubitril/valsartan compared with valsartan alone through 8 weeks (ratio of change 0.85; 95% CI 0.73–0.99; P=0.049; see Figure). Moreover, a beneficial effect of sacubitril/valsartan was seen in a secondary composite hierarchical outcome of (a) time to cardiovascular death, (b) number and timing of HF hospitalisations, (c) number and timing of urgent HF visits, and (d) time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8. The hierarchical outcome favoured sacubitril/valsartan but was not significant (unmatched win ratio 1.19; 95% CI 0.93–1.52; P=0.16). “Each component [of the composite endpoint] favoured sacubitril/valsartan,” Prof. Mentz said. Another positive effect of sacubitril/valsartan was the reduction of worsening renal function (odds ratio 0.61; 95% CI 0.40–0.93). However, with regard to safety, sacubitril/valsartan also increased symptomatic hypotension (OR 1.73; 95% CI 1.09–2.76).

Figure: Primary endpoint of the PARAGLIDE-HF trial (percentage change in NT-proBNP) [2]



CI, confidence interval; Sac/Val, sacubitril/valsartan.

Pre-specified subgroup analyses in patients with EF below normal (EF≤60%) showed that patients with an EF between 40 and 60% had a 22% greater reduction of NT-proBNP with sacubitril/valsartan compared with those with an EF of 60% or more. “There is a heterogeneous treatment effect in the below-normal EF group,” Prof. Mentz commented.

He explained that these results, particularly in light of similar findings from PARAGON-HF, provide additional support for a potential treatment benefit of sacubitril/valsartan in HF patients with an EF of 40% or more. Therefore, these results may influence future guidance for these patients, regardless of HF chronicity (i.e. acute and chronic vs de novo HF) and treatment setting.

1. Vaduganathan M, et al. J Am Coll Cardiol 2020;75:245–54.
2. Mentz RJ. PARAGLIDE-HF: Sacubitril/Valsartan versus valsartan on changes in NTproBNP, safety, and tolerability in patients with EF>40% stabilized after a WHF event. Session Late breaking clinical trials: medical therapy, Heart Failure 2023, 20–23 May, Prague, Czechia.
3. Mentz RJ, et al. J Am Coll Cardiol. 2023;May 21. DOI: 10.1016/j.jacc.2023.04.019. 

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Posted on 8 August 20238 August 2023