Real-World Outcomes of Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction

Abstract

Background: Sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor (ARNI), is a foundational therapy for heart failure with reduced ejection fraction (HFrEF), proven in randomized trials to reduce mortality and hospitalizations. However, translating these results into real-world clinical practice requires evaluation in broader, less selected patient populations. This study assessed the real-world effectiveness and safety of sacubitril/valsartan in patients with HFrEF, focusing on mortality, rehospitalization, functional improvement, and tolerability.

Methods: We conducted a retrospective cohort analysis of approximately 5,400 patients with HFrEF initiated on sacubitril/valsartan between 2016 and 2023. Data were collected from linked electronic health records and national registries, including baseline demographics, NYHA functional class, and laboratory parameters. The primary endpoints were all-cause mortality and heart failure–related hospitalizations, while secondary outcomes included changes in NYHA class and treatment-emergent adverse events such as renal dysfunction, hyperkalemia, and hypotension. Each patient’s outcomes after ARNI initiation were compared with their pre-treatment period, with subgroup analyses performed in older adults (≥75 years) and those with advanced functional limitation (NYHA III/IV).

Results: Over a mean follow-up of more than five years, initiation of sacubitril/valsartan was associated with significant clinical improvement. NYHA functional class improved markedly from baseline (p<0.0001), and the rate of cardiovascular and HF hospitalizations declined by more than 26% compared to the pre-ARNI period. These benefits were consistent across subgroups, including elderly patients and those with advanced disease. Importantly, all-cause mortality remained stable, with no signal of excess risk in high-risk subgroups. The treatment demonstrated good tolerability, as serious adverse events such as hypotension, renal impairment, or hyperkalemia were infrequent and aligned with the established safety profile of ARNI therapy.

Conclusion: This large real-world analysis reinforces the clinical value of sacubitril/valsartan in HFrEF, demonstrating sustained functional improvement, reduced hospitalizations, and favorable safety outcomes, supporting its continued integration into guideline-directed care.