Journal of Cardiac Failure 31 (2025) 721 724

Perspectives
Increasing Evidence Supports the Benefits of Rapid Uptitration of the Neurohormonal
Blockade in HFmrEF/HFpEF Patients With AHF
GAD COTTER, MD1,2 BETH DAVISON, PhD1,2 JAN BIEGUS, MD, PhD3
MATTEO PAGNESI, MD, PhD4 MARCO METRA, MD4 JAVED BUTLER, MD5,6
OVIDIU CHIONCEL, MD, PhD7 PIOTR PONIKOWSKI, MD, PhD4 and
ALEXANDRE MEBAZAA, MD, PhD1,8

Paris, France; Durham, North Carolina; Wroclaw, Poland; Italy; Texas; Jackson, Mississippi; Bucharest, Romania; and Paris, France

Despite evidence that the neurohormonal and adrenergic only after an AHF admission. I-PRESERVE (Irbesartan in
systems are significantly activated in heart failure (HF) Heart Failure with Preserved Ejection Fraction Study), which
patients with mildly reduced (HFmrEF) or preserved examined the other angiotensin receptor blocker irbesartan,
(HFpEF) ejection fraction (EF), many studies examining did not show its clinical benefit in stable HFpEF patients.5
the use of neurohormonal and adrenergic blockers in With regards to mineralocorticoid receptor antagonists
these populations failed to show substantial benefits.1 (MRA), although TOPCAT ( treatment of preserved cardiac
This activation is likely to be even higher in acute HF function heart failure with an aldosterone antagonist) did not
(AHF) settings or the peridischarge phase of the disease significantly reduce the incidence of the primary composite
than in a stable, chronic HF state. Thus, one may speculate outcome in patients with an left ventricular EF of 45%,6 it
that the potential benefits of the neurohormonal blockade did have a small effect when inappropriately enrolled
might be higher in the peridischarge period. patients in Georgia and Russia were excluded.7 In contrast,
No large prospective studies have evaluated the effects FINEARTS-HF (Finerenone in heart failure with mildly
of either beta-blockers (BBs) or angiotensin-converting reduced or preserved ejection fraction) recently showed that
enzyme inhibitors in patients with an EF of >40%.2 How- finerenone reduced the primary composite end point of
ever, some data exist with respect to other guideline- total worsening HF events or cardiovascular death com-
directed medical therapy components (Table 1). pared to placebo in patients with an EF of 40%.8 However,
Angiotensin receptor blockers were found to have posi- subsequent analysis has shown that the effects were entirely
tive effects in CHARM-PRESERVED (Effects of Candesar- driven by treatment effects in patients close to an AHF
tan in Patients With Chronic Heart Failure and Preserved admission, especially those within 7 days of such an admis-
Left-ventricular Ejection Fraction), which recruited sion, while the effects were very small to neutral in patients
a chronic HFpEF population.3 In the CHARM Program, >3 months from an AHF admission.9
even though candesartan’s effect on the primary end With respect to angiotensin-neprilysin inhibitors, PARA-
point was not significant in HFpEF, the risk of recurrent HF GON-HF (Prospective Comparison of ARNI with ARB
hospitalization was significantly lower in the candesartan Global Outcomes in HF with Preserved Ejection Fraction)
group, even in patients with preserved EF,4 suggesting failed to meet its primary end point,10 total hospitaliza-
that, in those patients, candesartan had protective effect tions for HF and death from cardiovascular causes;

From the 1Universit
e Paris Cit

e, INSERM UMR-S 942(MASCOT), Paris, Manuscript received November 25, 2024; revised manuscript received
France; 2Momentum Research Inc, Durham, North Carolina; 3Institute of December 16, 2024; revised manuscript accepted December 17, 2024.
Heart Diseases, Wroclaw Medical University, Wroclaw, Poland; Reprint requests: Gad Cotter, Momentum Research Inc., 1426 E NC
4
Cardiology, ASST Sedale Civili and Department of Medical and Surgical Highway 54, Suite B, Durham, NC, 27713 E-mail:
Specialties, Radiological Sciences, and Public Health, University of Gadcotter@momentum-research.com
Brescia, Italy; 5Baylor Scott and White Research Institute Dallas, Texas; See page 723 for disclosure information.
6
University of Mississippi Medical Center Jackson, Jackson, Mississippi; 1071-9164/$ - see front matter
7
Emergency Institute for Cardiovascular Diseases “Prof. C.C.Iliescu”; © 2025 The Author(s). Published by Elsevier Inc. This is an open access
University of Medicine “Carol Davila,” Bucharest, Romania and article under the CC BY license
8
Department of Anesthesiology and Critical Care and Burn Unit, Saint- (http://creativecommons.org/licenses/by/4.0/)
Louis and Lariboisiere Hospitals, FHU PROMICE, DMU Parabol, APHP. https://doi.org/10.1016/j.cardfail.2024.12.015
Nord, Paris, France.
722 Journal of Cardiac Failure Vol. 31 No. 4 April 2025

Table 1 The Impact of Different HF Therapies on Outcomes in AHF vs. CHF in Patients With Mildly Reduced or Preserved EF
AHF CHF
Beta-blocker No RCT data No RCT data
Angiotensin enzyme-con- No RCT data No RCT data
verting inhibitor
Angiotensin receptor CHARM-Program CHARM-PRESERVED
blocker Among patients with previous HF hospitalization: No effect on the primary outcome (cardiovascular death
The impact on the primary outcome (cardiovascular death or or HF hospitalization)
HF hospitalization) Lower risk of HF hospitalizations
HRs: 0.84 (5% CI 0.70 1.00) P < .05,
0.48 in HFmrEF (95% CI 0.33 0.70, P < .001), No Impact on CV death
0.78 in HFpEF (95% CI 0.59 1.03, P = .08)
Angiotensin-neprilysin PARAGON-HF PARAGON-HF
inhibitors Patients post HF episode No effect on the primary composite outcome
(30 days) Never hospitalized
Absolute risk reduction 6.4% Absolute risk reduction 0.02%
MRA FINEARTS-HF TOPCAT
Finerenone lowered the risk of the primary composite out- No effect on the primary composite outcome
come in those enrolled within 7 days of WHF (RR 0.74, 95% HR:
CI 0.57 0.95) or between 7 days and 3 months of WHF 1.78 (95% CI 1.48 2.13, P < .001) in the Americas cohort
FINEARTS-HF
No impact on the primary outcome among patients >3
months from WHF or without prior WHF (RR 0.99, 95%
CI 0.81 1.21)
Comprehensive neurohor- STRONG-HF
monal blockade (beta- The primary composite end point in patients with EF >40%
blocker, RASi, MRA) The risk difference 12.5% (95% CI 3.7% 21.3%)
AHF, acute heart failure; CHF, chronic heart failure; CI, confidence interval; CV, cardiovascular; EF, ejection fraction; HF, heart failure; HFpEF, heart failure with preserved
ejection fraction; HFmrEF, heart failure with midrange ejection fraction; HR, hazard ratio; MRA, mineralocorticoid receptor antagonist; RASi, renin angiotensin system inhibi-
tor; RCT, randomized, controlled trial; RR, risk ratio; WHF, worsening heart failure.

however, most patients enrolled in PARAGON-HF were STRONG-HF study were simultaneously up-titrated on
enrolled during the stable phase of chronic HF. However, three types of therapy (RASi, BBs, and MRAs), whereas in
a significant effect was observed in PARAGON-HF in FINEARTS-HF they were only given MRA vs placebo;
patients enrolled closer to an AHF, although the P value therefore, it is possible that the greater effect size
for interaction was .15.11 This finding was confirmed by a observed in STRONG-HF may be due to the fact that 3
recent prespecified meta-analysis of the PARAGON-HF medications addressing neurohormonal and adrenergic
and PARAGLIDE-HF (Prospective comparison of ARNI activations were given simultaneously. Therefore, the
with ARB Given following stabiLization In DEcompensated results of FINEARTS-HF in patients close to an AHF epi-
HFpEF) studies,12 which showed significant effects in sode are similar, although smaller in magnitude, to those
patients close to an AHF event. observed in the STRONG-HF patients with HFmrEF and
Finally, a subanalysis of STRONG-HF (Safety, Tolerabil-
ity, and Efficacy of Rapid Optimization, Helped by NT-
proBNP Testing, of Heart Failure Therapies) that exam-
ined the role of rapid uptitration of guideline-directed
medical therapy, mostly inclusive of RASi, BB, and MRAs,
has found large effects of this strategy in patients with
AHF and an EF of >40%, with the effects numerically even
surpassing those seen in patients with an EF of 40%.13
The primary composite end point in STRONG-HF in
patients with an EF of >40% (i.e., HFmrEF and HFpEF)
occurred in 10.7% in the high-intensity care group and in
23.3% in the usual care group (risk difference 12.5%, 95%
CI 3.7% 21.3%). Of note, in FINEARTS-HF, the inciden-
ces of first HF readmission or death in patients enrolled
within 7 days of an AHF event (similar to the inclusion cri-
teria in the STRONG-HF study) were 13.5 events/100
patient-years in the finerenone arm vs 16.3 events/100 Fig. 1. Results of the FINEHEART-HF study by time from acute heart fail-
patient-years in the control arm. Although cross-study ure (AHF) event. ARR, adjusted risk ratio; CI, confidence interval; EF,
comparisons are not possible, the patients enrolled in the ejection fraction; WHF, worsening heart failure.
 COTTER et al  Increasing Evidence Supports the Benefits 723

HFpEF (Fig. 1), although the data on the effects of finere- HFmrEF or HFpEF, both angiotensin-neprilysin inhibitors
none in FINERARTS-HF in patients who were enrolled >3 and MRA/finerenone may be through targeting neurohor-
months from an AHF admission are very similar to those monal activation, which is particularly activated in AHF. A
from TOPCAT. combination of angiotensin-neprilysin inhibitors/MRA-
Of note, retrospective data from observational studies finerenone/SGLT2i as a potentially optimal approach to
in AHF showed a significant reduction in mortality in be started as early possible after stabilization across the
patients treated with RASI and BB. The results of the larg- whole spectrum of left ventricular EF. The results of
est AHF meta-analysis, using data from the 285 studies STRONG-HF suggest that combining those drugs may fur-
and including >15 million AHF hospitalizations demon- ther add to the benefit of each of these therapies, espe-
strated the association between increased use of BB and cially when uptitrated rapidly. The same conclusion is not
RASIs at hospital admission for AHF with any EF and well-supported by available data in patients with HFmrEF
reduction in mortality.14 The results were replicated in and HFpEF who are in the chronic HF phase (>3 months
another study, where BBs and RASIs at discharge, alone or from an AHF event), where neurohormonal activation is
in combination, were associated with a consistent reduction expected to be smaller, with both the results of PARA-
in mortality in patients with recent AHF, regardless of left GON-HF and FINEARTS-HF suggesting smaller effect
ventricular EF or the presence of comorbidities.15 sizes, also supported by the smaller effect sizes observed
in CHARM-PRESERVED, I-PRESERVE, and TOPCAT in
One must contextualize the current results vis-
a-vis the chronic HF patients. In those patients, treatment with
effects observed in stable, chronic HF with HFmrEF/ SGLT inhibitors and glucagon-like peptide-1 receptor
HFpEF patients treated with sodium-glucose cotrans- agonists may be of higher value. How long neurohor-
porter (SGLT) inhibitors and, recently, glucagon-like pep- monal blockers will be effective in patients with HFmrEF
tide-1 receptor agonists, both of which have exerted and HFEPF is not clear. In STRONG-HF, the patients were
highly beneficial effects in stable chronic HF patients with followed for 180 days, and the effects seemed to continue
high EF.16 20 SGLT inhibitors were also shown to be effec- and diverge over time; the same can be said about
tive in AHF with HFmrEF and HFpEF patients,21,22 with FINEARTS-HF, where visual examination of the
empagliflozin being shown in EMPULSE (Empagliflozin in Kaplan Meier curves suggests that the curves continue
Patients Hospitalized for Acute Heart Failure) to be effec- to diverge over the first year, at least. Therefore, it seems
tive across the full EF spectrum in patients with AHF.23 that neurohormonal blockade should be given to patients
Therefore, SGLT inhibitors and glucagon-like peptide-1 with HFmrEF and HFEPF for 1 year after an AHF admis-
agonists are probably effective in HFmrEF and HFpEF in sion and beyond.
chronic HF patients. For SGLT inhibitors, evidence already
exists that they are also effective in AHF patients and, Those contrasting results highlight the differences
therefore, should be started during or immediately after between AHF and chronic HF patients, especially those
an AHF event.21,22 with HFmrEF/HFpEF. In the acute state, where neurohor-
monal adrenergic activation is more pronounced, rapid
Taken together (Fig. 2), these results suggest that uptitration of quadruple guideline-directed medical ther-
the effectiveness of treatment of patients with AHF and apy is now well-supported by evidence from prospective
clinical trials and should be adopted by guidelines and
implemented.

Disclosures

GC and BD are directors of Heart Initiative, a non-profit

organization, and are employees of Momentum Research,
which has received grants for research from Abbott Labo-
ratories, Amgen, Celyad, Cirius Therapeutics, Corteria
Pharmaceuticals, Heart Initiative, Sanofi, Windtree Thera-
peutics, and XyloCor Therapeutics. JB has received hono-
raria from Bayer, Boehringer Ingelheim, and AstraZeneca
for lectures. PP has nothing to declare. OC serves on an
advisory board for Boehringer Ingelheim. MP has received
personal fees from Abbott Vascular, AstraZeneca, Boeh-
Fig. 2. Effects of medications on outcomes in acute heart failure (AHF) ringer Ingelheim, Novartis, Roche Diagnostics, and Vifor
and chronic heart failure (CHF) owing to HF with midrange ejection frac- Pharma. MM has received personal fees since January,
tion and HF with preserved ejection fraction. ACEI, angiotensin-convert-
ing enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, 2021, from Actelion, Amgen, Livanova, and Vifor Pharma
angiotensin-neprilysin inhibitor; BB, beta-blocker; GLP-1a, glucagon-like as a member of the executive or data monitoring commit-
peptide 1a; SGLT-2i, sodium-glucose cotransporter 2 inhibitor. tees of sponsored clinical trials and from AstraZeneca,
724 Journal of Cardiac Failure Vol. 31 No. 4 April 2025

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