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ARNI Bests ARB to Reduce NT-proBNP in Stabilized Preserved-EF HF

Marilynn Larkin

May 25, 2023

Patients with an ejection fraction (EF) greater than 40% who were stabilized after
recent worsening or de novo heart failure (HF) had a greater reduction in
natriuretic peptides, less worsening renal function, but a higher rate of
hypotension over 8 weeks with sacubitril-valsartan (Entresto) vs valsartan (Diovan)
in the PARAGLIDE-HF trial.

A subgroup analysis showed evidence of a larger treatment effect among those with
an EF of 60% or less, said Robert Mentz, MD, of the Duke Clinical Research
Institute, Durham, North Carolina.

Mentz presented the findings May 21 at the European Society of Cardiology's

scientific congress, Heart Failure 2023. The study was also published online
simultaneously in the Journal of the American College of Cardiology.

"Next steps will involve further assessment of the cardiovascular and renal
benefits, as well as further exploration of the symptomatic hypotension that we
observed," Mentz told theheart.org | Medscape Cardiology.

Meanwhile, he said, "Clinicians should be aware of these new data — specifically,

the incremental reduction in natriuretic peptide level compared with valsartan and
potential benefits on cardiovascular and renal events," particularly in those with
an EF >40% to ≤60%.

Larger Benefit for EF >40% to <60%

PARAGLIDE-HF was a double-blind, randomized controlled trial with 466 patients with
EF >40% enrolled within 30 days of a worsening HF event. The median age was 71
years, 52% were women, and 22% were Black.

The trial was a follow-up to PARAGON-HF, which had shown that in patients with an
EF ≥45%, sacubitril-valsartan did not result in a significantly lower rate of total
hospitalizations for HF or death from cardiovascular causes compared with
valsartan.

The primary endpoint for PARAGLIDE was the time-averaged proportional change in NT-
proBNP from baseline through weeks 4 and 8, as in the PIONEER-HF trial. That trial
showed that among patients hospitalized for acute decompensated HF with reduced EF
(<40%), the angiotensin receptor/neprilysin inhibitor (ARNI) led to a greater
reduction in NT-proBNP concentration than the angiotensin receptor blocker (ARB).

Similarly, for PARAGLIDE, the time-averaged reduction in NT-proBNP was greater with
sacubitril-valsartan, with a change ratio of 0.85 (15% greater reduction).

A secondary hierarchical outcome for PARAGLIDE, using the win ratio, consisted of
a) time to cardiovascular death, b) number and timing of HF hospitalizations, 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 favored sacubitril-valsartan, but was not significant

(unmatched win ratio, 1.19).
As noted, sacubitril-valsartan reduced worsening renal function compared to
valsartan (odds ratio, 0.61) but increased symptomatic hypotension (OR, 1.73).

"We will work to better characterize the hypotension events that were observed to
help identify those patients at greater risk and to provide further clarity around
the timing and implications of these events," Mentz told theheart.org | Medscape
Cardiology.

The team hypothesizes that such events may be prevented by optimizing volume status
and background therapies commonly used to treat hypertension in these patients.

"For instance," Mentz suggested, "calcium channel blockers like amlodipine could be
dose-reduced or discontinued in patients with lower baseline blood pressures to
better support sacubitril/valsartan initiation and titration."

He highlighted the subgroup analysis showing evidence of a larger treatment effect

in study patients with an EF of 60% or less for the NT-proBNP change (0.78) and the
hierarchical outcome (win ratio, 1.46).

"These data may influence future guidance for sacubitril-valsartan in HF with

EF>40%, regardless of HF chronicity (acute or chronic vs de novo) and treatment
setting (hospital vs clinic)," Mentz concluded.

Data "Far from Conclusive"

Sean Pinney, MD, chief of cardiology at Mount Sinai Morningside in New York City,
commented on the study for theheart.org | Medscape Cardiology. The results "help
expand the current evidence base supporting the use of an ARNI in patients" with an
EF >40% up to 60%, and "provide confidence that ARNIs help to lower natriuretic
peptides."

"It comes as little surprise that not everyone was able to tolerate these
medications due to intolerable side effects like dizziness or hypotension," he
said.

Nevertheless, he added, "Hopefully, these trial data help strengthen clinicians'

resolve to prescribe sacubitril/valsartan to a growing population of vulnerable
patients."

In a related editorial, Hector O. Ventura, MD, of the Ochsner Clinical School-

University of Queensland School of Medicine, New Orleans, Louisiana, and colleagues
express several concerns about the study.

Although the trial achieved significance for the primary endpoint, the margin of
benefit was less than expected and the magnitude of the NT-proBNP reduction may not
have been enough to reach the threshold for clinical benefit, they write.

Diuretic dosing in the two groups was not reported, and between-group differences
may have contributed to both the differential NT-proBNP reduction and the rates of
hypotension.

Furthermore, the sacubitril-valsartan group had a higher proportion of missing NT-

proBNP data, which may have biased the results.

"In aggregate," they write, "while the study suggests some evidence of a beneficial
trend of sacubitril-valsartan in HFpEF and a recent episode of worsening HF, the
data are far from conclusive."
"Clinicians who elect to use sacubitril-valsartan in this population should be
mindful of the risk for hypotension and select patients carefully, while providing
close ambulatory follow up to ensure stability and adherence," they note.

"This important trial provides some wins that support selective use of sacubitril-
valsartan in HFpEF [as well as] observed losses, which too may help to define
better implementation strategies in appropriately selected patients," the
editorialists conclude.

The study was funded by Novartis. Mentz and other co-authors have received fees
from the Novartis. Pinney, Ventura, and the other editorialists disclosed no
relevant financial relationships.

Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023.

Presented May 21, 2023.

J Amer Coll Cardiol. Published online May 21, 2023. Full text, Editorial

Follow Marilynn Larkin on Twitter: @MarilynnL .

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Medscape - May 25, 2023.