ARNI in HF With Mildly Reduced or Preserved EF and Worsening HF

Quick Takes

  • In a randomized trial of HF patients with EF >40% with worsening HF comparing sacubitril/valsartan (SV) to valsartan, time-averaged reduction in NT-proBNP was greater in the SV group with difference notable within week 1.
  • Clinical endpoints were only statistically different with SV compared with valsartan in patients with EF <60%, but the trial was underpowered for clinical endpoints.
  • SV was associated with a slower decline in renal function but with more symptomatic hypotension, and a larger proportion of patients discontinued SV than valsartan.

Study Questions:

What is the safety and efficacy of angiotensin-neprilysin inhibition (ARNI) in patients with ejection fraction (EF) >40% after a worsening heart failure (WHF) event?


PARAGLIDE-HF is a multicenter, double-blind, randomized trial and enrolled patients with EF >40% either during or within 30 days of either heart failure (HF) hospitalization/emergency room visit or urgent HF visit needing intravenous (IV) diuretics. Patients needed to be stable with a systolic blood pressure >100 mm Hg with no increase in IV diuretics without IV inotropes/vasodilators. In total, 466 patients were randomized to sacubitril/valsartan (SV) versus valsartan alone. The primary endpoint included time-averaged proportional change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) from baseline to weeks 4 and 8. The secondary outcome included a hierarchical outcome consisting of 1) time to cardiovascular death, 2) number and timing of HF rehospitalizations, 3) number and timing of urgent HF visits, and 4) primary outcome.


Overall, 52% of patients were women, 22% were Black, and mean age was 70 years, with a median EF of 55%. Over a mean duration of follow-up of 7.9 months, time-averaged reduction in NT-proBNP was greater in the SV group with difference notable within week 1. The secondary hierarchical outcome was no different between the two groups. In the prespecified group with EF ≤60%, a larger change was noted in the primary outcome with a statistically significant difference in the secondary outcome. For safety endpoints, patients on SV had less worsening renal function but with more symptomatic hypotension. Rates of hyperkalemia were similar between the two groups. Study drug discontinuation was more common with SV (33%) than valsartan (18%).


In a randomized trial of patients with EF >40% stabilized after WHF, SV use was associated with lower NT-proBNP at week 8 compared with valsartan alone without a difference in clinical endpoints. Renal function declined slower in the SV group but there was a higher risk for hypotension. The subgroup of patients with EF ≤60% had a larger change in NT-proBNP and clinical endpoint benefit with SV.


Advances made in HF with reduced EF (HFrEF) have yet to translate to patients with HF with preserved EF (HFpEF). This trial provides data in patients with higher-risk HFpEF than studied to date in trials examining the efficacy of ARNI. Notable characteristics of enrolled patients include a large proportion of Black patients, obese individuals, and inclusion needing destabilized HFpEF. While ARNI use was associated with a reduction in NT-proBNP within 1 week, clinical endpoints were not statistically significant, but ARNI had a nephroprotective effect compared with valsartan. It is important to note that the trial was not powered for clinical endpoints. Similar to previous trials with ARNI in HFpEF, the patients benefitting the most were HF patients with an EF <60%. ARNI was notably discontinued by one third of patients and rates of symptomatic hypotension were much higher compared with valsartan.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Angiotensins, Blood Pressure, Diuretics, Heart Failure, Hyperkalemia, Hypotension, Natriuretic Peptide, Brain, Neprilysin, Patient Readmission, Renal Insufficiency, Stroke Volume, Valsartan, Vasodilator Agents

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