Available online 21 April 2025

Author links open overlay panel, , , , , , , ABSTRACTBackground

: n the PARAGLIDE-HF trial, treatment with sacubitril/valsartan (Sac/Val) was associated with greater reduction in NT-proBNP than valsartan (Val) alone in patients stabilized after an episode of worsening heart failure (HF) with left ventricular ejection fraction (LVEF) >40%. Treatment effects were most apparent in the subgroup with LVEF below normal (≤60%). This pre-specified analysis sought to compare the detailed treatment effects and adverse event profiles of Sac/Val vs. Val in patients with LVEF ≤60% vs. >60%.

Methods

: Baseline demographics and clinical characteristics were compared between patients with baseline LVEF ≤60% vs. >60%. Rates of recurrent composite events (adjudicated CV death, HF hospitalizations, and urgent HF visits) were compared between groups using a semi-parametric proportional rates model. These recurrent composite events were also analyzed across the continuous LVEF spectrum using restricted cubic splines. Incidence of adverse events were analyzed using a logistic regression model with LVEF ≤60% vs. >60%, treatment arm, and in-hospital/out-of-hospital randomization as covariates. The interaction of LVEF category and treatment arm was assessed for all models

Results

: Compared to those with LVEF >60%, patients with LVEF ≤60% were younger with lower NYHA class, but similar NT-proBNP values at baseline and similar co-morbidity burden. Among patients with LVEF ≤60%, those treated with Sac/Val experienced fewer recurrent composite events compared to those treated with Val (rate ratio 0.60 [95% CI: 0.37-0.99], p=0.046); predominantly driven by HF hospitalizations. Patients with LVEF >60% treated with Sac/Val vs. Val demonstrated similar rates of recurrent composite events (RR 1.46 [0.77-2.79], p=0.24) (interaction p-value = 0.032). This was consistent with the continuous analysis in which patients treated with Sac/Val were significantly less likely to have events compared with patients with Val at LVEF values below 58%. Patients with LVEF >60% treated with Sac/Val experienced more symptomatic hypotension (OR 3.55 [95% CI: 1.35-9.37], p=0.01) compared to those treated with Val, whereas rates of symptomatic hypotension were comparable across treatment groups in patients with LVEF ≤60% (OR 1.36 [0.79-2.32], p=0.27, interaction p-value 0.09).

Conclusions

: Compared to treatment with Val in patients with worsening HF and LVEF>40%, treatment with Sac/Val is associated with greater clinical benefit in those with LVEF ≤60% than in those with LVEF >60%.

Clinical Trial Registration

: Clinicaltrials.gov identifier, NCT03988634

Section snippetsINTRODUCTION

Many pharmacologic therapies for patients with heart failure (HF) demonstrate heterogeneity in treatment effect across the left ventricular ejection fraction (LVEF) spectrum. Subgroup analyses as well as meta-analyses support the consideration of angiotensin receptor blockers,1 mineralocorticoid receptor antagonists,2 beta blockers,3 and angiotensin receptor-neprilysin inhibitors (ARNi) beyond LVEF <40%, in particular for patients with HF with mildly reduced ejection fraction (HFmrEF, LVEF

Trial Design

The trial design,5 baseline characteristics,5 and primary results6 have been previously reported. Briefly, PARAGLIDE-HF was a multicenter, double-blind, randomized controlled trial that investigated the effect of Sac/Val vs. Val on changes in NT-proBNP, safety, and tolerability in patients with HFmrEF or HFpEF following stabilization from a WHF event. Patients were randomly assigned 1:1 to sacubitril/valsartan titrated to a target dose of 97/103 mg twice daily versus valsartan titrated to 160

RESULTS

Of 466 trial participants, 357 (76.6%) had LVEF ≤ 60% and 109 (23.3%) had LVEF > 60%. Baseline characteristics stratified by LVEF group are summarized in Table 1. Compared to those with LVEF >60%, patients with LVEF ≤60% were younger (median age 70 vs. 73 years old) with lower NYHA class (50.8% vs. 36.7% class I-II) and were more likely to have a predominant ischemic HF etiology (29.5% vs. 16.4%). Patients in each group demonstrated similar NT-proBNP values at baseline and similar co-morbidity

DISCUSSION

In this pre-specified analysis of patients with LVEF >40% stabilized after a recent WHF event, treatment with Sac/Val was associated with greater clinical benefit than treatment with Val among those with LVEF ≤60% as compared to those with LVEF >60%. In contrast, symptomatic hypotension was more common in patients with worsening HF and LVEF>60% treated with Sac/Val as compared to those with LVEF ≤60%. These data indicate that Sac/Val may be utilized most efficaciously and safely in patients

CONCLUSIONS

Treatment with Sac/Val was associated with greater clinical benefit compared with Val alone among those with LVEF ≤60% as compared to those with LVEF >60% in patients with HFmrEF/HFpEF stabilized after a recent WHF event. Adverse event profiles were similar except for symptomatic hypotension, which was more common in patients with worsening HF and LVEF>60% treated with Sac/Val as compared to with Val alone, but similar among those with LVEF ≤60% treated with Sac/Val or Val.

DISCLOSURES

Dr. Peters has been supported by the National Heart Lung and Blood Institute (T32HL069749) and has received honoraria from Cytokinetics. Drs. Ward and Williamson were employees of Novartis. Dr Zieroth has received research grant support, served on advisory boards for, or has had speaker engagements with Abbott, Akcea AstraZeneca, Amgen, Alnylam, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Servier,

FUNDING SOURCES

PARAGLIDE-HF and pre-specified analyses funded by Novartis Pharmaceuticals Corporation. ClinicalTrials.gov number, NCT03988634

CRediT authorship contribution statement

Anthony E Peters: Writing – review & editing, Writing – original draft, Supervision, Methodology, Investigation, Conceptualization. Shuang Li: Methodology, Formal analysis, Data curation. Derek Cyr: Writing – review & editing, Supervision, Methodology. Kristin M. Williamson: Conceptualization. Shelley Zieroth: Writing – review & editing, Conceptualization. Marat Fudim: Writing – review & editing, Supervision, Methodology, Conceptualization. Jonathan H. Ward: Writing – review & editing,

ACKNOWLEDGEMENTS

None

REFERENCES (18)

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