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Combination of Sacubitril/Valsartan May Improve Heart Failure Outcomes


In patients with ejection fraction greater than 40% who were stabilized after a worsening heart failure event, use of combination sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels compared with valsartan alone.

In patients with ejection fraction (EF) greater than 40% who were stabilized after a worsening heart failure (WHF) event, sacubitril/valsartan (sac/val) led to greater reduction in plasma NT-proBNP levels, according to a study published in the Journal of the American College of Cardiology.

The use of sac/val was associated with clinical benefit compared with only valsartan, but also an increase in symptomatic hypotension.1

This study was conducted because US guidelines recommend consideration of sac/val in chronic HF and mildly decreased or preserved EF. However, it’s not yet known whether this initiation is safe and effective in patients with EF greater than 40% after a WHF event.

“The PARAGLIDE-HF trial was designed to assess the efficacy, safety, and tolerability of sac/val vs val in a diverse population of patients with EF >40% and a recent WHF event,” the researchers wrote. This trial followed the PARAGON-HF trial.

PARAGLIDE-HF was a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients with EF greater than 40% enrolled within 30 days of a WHF event. The primary end point was time-averaged proportional change in amino terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. A secondary composite hierarchical outcome consisted of cardiovascular death, HF hospitalizations, urgent HF visits, and change in NT-proBNP.

A total of 466 patients were randomized to receive either sac/val (n = 233) or val (n = 233) from June 2019 through October 2022. Of these patients, 52% were women, 22% were Black, and the mean (SD) age was 70 (12) years.

Time-averaged reduction in the NT-proBNP was higher with sac/val (ratio of change, 0.85; 95% CI, 0.73-.999; P = .049). The hierarchical outcome preferred sac/val but was not significant (unmatched win ratio, 1.19; 95% CI, 0.93-1.52; P = .16).

Sac/val diminished the odds of worsening renal function (odds ratio [OR], 0.61; 95% CI, 0.40-0.93) but increased the odds of symptomatic hypotension (OR, 1.73; 95% CI, 1.09-2.76). There was proof of a larger treatment effect in the subgroup with EF of at least 60% for NT-proBNP change (0.78; 95% CI, 0.61-0.98) and the hierarchical outcome (win ratio, 1.46; 95% CI, 1.09-1.95).

Because of the similar findings from the PARAGON-HF trial, the researchers think that these new data give additional support for the clinical benefits of combined angiotensin receptor neprilysin inhibition in patients with HFpEF, especially among those with below-normal EF.

The trial met its primary end point, which the researchers labeled as important because it validates the incremental effect of concomitant neprilysin inhibition over just angiotensin inhibition in patients with HF and EF greater than 40%.

Additionally, secondary end points showed a favorable trend to sac/val, even if formal criteria weren’t met for statistical significance, which was consistent with findings from PARAGON-HF.

Results seen in PARAGON-HF and PARAGLIDE-HF suggest together that combined angiotensin receptor neprilysin inhibition is probably more effective than angiotensin receptor blockage alone in treatment of patients with HF and EF greater than 40%, regardless of care setting, with a larger benefit when EF is below normal.

The broad population included in PARAGLIDE-HF improves the generalizability of these data to similar patients seen in routine practice.

“Thus, these data provide important insights regarding the effect of Sac/Val in diverse populations not historically represented well in clinical trials,” the researchers wrote.

Some limitations of this study include its modest sample size, and the fact that the study was not powered for clinical events. Follow-up duration was also short compared with PARAGON-HF.

“These data add to the evidence supporting a potential treatment benefit of sacubitril/valsartan in patients with EF over 40% and particularly in those with EF below normal (≤60%). The findings may influence future guidance for the use of the drug in this population, both in and out of hospital and for those with acute, chronic or de novo heart failure,” said principal investigator Robert Mentz, MD, of Duke University Medical Center, in a press release.2


1. Mentz RJ, Ward JH, Hernandez AF, et al. Angiotensin-neprilysin inhibition in patients with mildly reduced or preserved ejection fraction and worsening heart failure. J Am Coll Cardiol. Published online May 21, 2023. doi:10.1016/j.jacc.2023.04.019

2. Sacubitril/valsartan shows benefit in heart failure with ejection fraction above 40%. News release. EurekAlert! May 21, 2023. Accessed June 5, 2023. https://www.eurekalert.org/news-releases/989642

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