Influence of ejection fraction on outcomes with sacubitril/valsartan in patients with worsening heart failure with EF>40%: The PARAGLIDE-HF Trial.

BACKGROUND: In 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 prespecified 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 = .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 = .24) (interaction P-value = .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 = .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 = .27, interaction P-value .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.

Duke Scholars

Author Marat Fudim Medicine, Cardiology

Author Robert John Mentz Medicine, Cardiology