PARAGLIDE-HF Offers Further Insight into Sacubitril/Valsartan in Heart Failure with Elevated EF


Presented at ESC HFA 2023, results of PARAGLIDE-HF detail the effects of sacubitril/valsartan on NT-proBNP and multiple clinical outcomes, relative to valsartan alone, in patients with HFmrEF or HFpEF.

Robert Mentz, MD | Credit: Duke University Medical Center

Robert Mentz, MD
Credit: Duke University Medical Center

For recently stabilized patients with heart failure with an elevated ejection fraction, use of sacubitril/valsartan (Entresto) was associated with greater reduction in plasma NT-proBNP levels and greater clinical benefit than valsartan alone, but was also associated with increased risk of symptomatic hypotension.

Presented at the European Society of Cardiology’s 2023 Heart Failure Association meeting, results of the trial support guideline recommendations for consideration of sacubitril/valsartan in patients with heart failure with an ejection fraction greater than 40% as well as offering confirmatory evidence of the potential for increased treatment benefit observed in patient subgroups within the PARAGON-HF trial.

“These data add to the evidence supporting a potential treatment benefit of sacubitril/valsartan in patients with [ejection fraction] over 40% and particularly in those with [ejection fraction] 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 study presenter Rob Mentz, MD, associate professor of medicine and chief of the Heart Failure Section at Duke University Medical Center.2

The management of heart failure, particularly heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF), has undergone a historic revolution in the last decade. In February 2021, sacubitril/valsartan cemented itself as a cornerstone of management for this patient population, with a US Food and Drug Administration approval making the agent the first therapy approved for heart failure patients across the spectrum of ejection fraction.3

The February 2021 approval was based on data from the PARAGON-HF trial, which missed achieving statistical significance for its primary composite endpoint of worsening heart failure or cardiovascular death (Rate ratio, 0.87 [95% confidence interval [CI] 0.75–1.01; P = .059). From analyses of the trial, a trend towards greater benefit was observed among a patient subgroup with an ejection fraction of emerged.3

Based on this apparent trend towards increased benefit, the PARAGLIDE-HF trial screened 586 stabilized patients with an ejection fraction greater than 40% and elevated NT-proBNP or B-type natriuretic peptide within 30 days of a worsening heart failure event. Designed as a multicenter, double-blind, randomized controlled trial, the trial’s primary endpoint was the time-averaged proportional change in NT-proBNP from baseline through weeks 4 and 8. Investigators noted the trial’s secondary hierarchical outcome consisted of cardiovascular death, heart failure hospitalizations, urgent heart failure visits, and change in NT-proBNP.1

Per trial protocol, patients were randomized in a 1:1 ratio to sacubitril/valsartan titrated to a target dose of 97/103 mg twice daily or valsartan titrated to 160 mg twice daily. Investigators noted study visits were to occur at week 1, week 4, week 8, and then approximately every 16 weeks.1

Of the 586 adult patients who underwent screening, 466 underwent randomization, with 233 assigned to each treatment arm. The overall study cohort had a mean age of 70 (SD, 12) years, 52% were women, and 22% were Black. Investigators pointed out the cohort had a median ejection fraction of 55% (IQR, 50-60), 33% had de novo heart failure, and the median screening NT-proBNP was 2009 (IQR, 1291-3813) pg/mL. The baseline characteristics were similar between the groups.1

Upon analysis, results indicated the time-averaged reduction in NT-proBNP was greater among the sacubitril/valsartan group than the valsartan arm (ratio of change, 0.85 [95% CI, 0.73-0.999]; P=.049). Further analysis indicated the win ratio for the hierarchical outcome favored the sacubitril/valsartan group but failed to reach statistical significance (unmatched win ratio, 1.19 [95% CI, 0.93-1.52]; P = .16). Investigators highlighted use of sacubitril/valsartan was associated with a reduction in worsening renal function (Odds ratio [OR], 0.61 [95% CI, 0.40-0.93]) but an increase in symptomatic hypotension (OR, 1.73 [95% CI, 1.09-2.76]) relative to valsartan alone.1

Investigators called attention to evidence of a larger treatment effect among a subgroup of patients with an ejection fraction equal to or less than 60%, with a ratio of change of 0.78 (95% CI, 0.61-0.98) for NT-proBNP change and a win ratio of 1.46 (95% CI, 1.09-1.95) for the hierarchical outcome.1

In an editorial published in the Journal of the American College of Cardiology, Hector O. Ventura, MD, Carl J. Lavie, MD, and Mandeep R. Mehra, MD, MSc, caution the over interpretation of results from the PARAGLIDE-HF trial and suggest the results could indicate the benefit of NT-proBNP reduction may not confer as significant a clinical benefit as once believed. The trio also noted the need for additional investigation of the interation between sacubitril/valsartan and SGLT2 inhibitors, given the latter's ascent into guideline recommendations.4

“This important trial provides some wins that support selective use of sacubitril-valsartan in HFpEF while other observed losses which too may help to define better implementation strategies in appropriately selected patients. Furthermore, additional studies are needed to elucidate the combined benefits of angiotensin-neprilysin inhibition and SGLT2 inhibitors across various stages of HFpEF,” wrote the trio.4


  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. Journal of the American College of Cardiology. 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%. European Society of Cardiology. May 21, 2023. Accessed May 21, 2023.
  3. Campbell P. FDA expands label for Sacubitril/Valsartan (entresto) to include some HFPEF patients. HCP Live. February 16, 2021. Accessed May 21, 2023.
  4. Ventura HO, Lavie CJ, Mehra MR. Angiotensin-NEPRILYSIN inhibition in heart failure with preserved ejection fraction: You win some, you lose some. Journal of the American College of Cardiology. Published online May 21, 2023. doi:10.1016/j.jacc.2023.05.002
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