Sacubitril/Valsartan in Heart Failure with Mildly Reduced Ejection Fraction: A Subgroup Meta-Analysis of PARAGLIDE-HF and PARAGON-HF

Abstract

Introduction: Sacubitril/valsartan (S/V) is established for heart failure with reduced ejection fraction (HFrEF, EF≤40%) and preserved EF (HFpEF, EF≥50%). Its role in mildly reduced EF (HFmrEF, EF 41–49%) is less defined. This meta-analysis pools data from two large trials focusing on HFmrEF subgroups.
Methods: Patient-level subgroup meta-analysis of PARAGLIDE-HF and PARAGON-HF (n total 9,802). Inclusion: EF 41–49%, NYHA II–III, elevated natriuretic peptides. Primary outcome: total heart failure hospitalizations and cardiovascular death (first event).
Results: Among 1,244 HFmrEF patients, S/V reduced primary outcome (rate ratio 0.79, 95% CI 0.66–0.94, p=0.008) compared to valsartan alone (PARAGON) or enalapril (PARAGLIDE). Benefit was consistent for EF 41–44% (RR 0.77) and 45–49% (RR 0.81). Kansas City Cardiomyopathy Questionnaire (KCCQ) improved by 4.2 points (p=0.01). Hypotension (systolic <90 mmHg) occurred in 12.8% vs 8.2% in control.
Discussion: The continuous benefit across EF spectrum suggests S/V should be considered in HFmrEF. The effect size is smaller than in HFrEF (RR 0.79 vs 0.68 in PARADIGM-HF). Limitations include post-hoc nature and relatively small HFmrEF sample.
Conclusions: Sacubitril/valsartan reduces hospitalizations and improves quality of life in HFmrEF, supporting EF-agnostic treatment in select patients.