Sacubitril/Valsartan Compared With ACE Inhibitors or Angiotensin Receptor Blockers Across Ejection Fraction Levels: A Real-World Multistate Cohort Study

By
MICHEL CHEDID EL HELOU
KARIM HOYEK
HARSH PATOLIA
MICHAEL HILL
ZIAD ZALAQUETT
HUNTER BLOCK-BEACH
ASHISH SARRAJU
AMANDA R. VEST
NANCY M. ALBERT
RANDALL C. STARLING
TREJEEVE MARTYN
October 10, 2026

Journal Of Cardiac Failure

Overview

This retrospective electronic health record cohort includes 25,333 adults with heart failure and compares sacubitril/valsartan, an angiotensin receptor/neprilysin inhibitor (ARNI), with ACE inhibitor or angiotensin receptor blocker (ACEi/ARB) therapy across left ventricular ejection fraction (LVEF) levels. ARNI use is associated with lower adjusted risk of all-cause death or first all-cause hospitalization, without a significant treatment-by-LVEF interaction. Findings at LVEF ≥60% remain hypothesis-generating.

Background

Sacubitril/valsartan is an established therapy for heart failure with reduced EF, based on PARADIGM-HF. Evidence at higher LVEF is less definitive. PARAGON-HF is neutral overall, although treatment effects favor women and participants below the trial median LVEF of 57%. Pooled PARADIGM-HF and PARAGON-HF analyses show attenuation of treatment effect as LVEF increases.

PARAGLIDE-HF and pooled PARAGLIDE-HF/PARAGON-HF analyses show greater benefit at LVEF ≤60%, particularly after recent worsening heart failure. This study evaluates treatment use and associated outcomes in contemporary practice.

Data Highlights

Measure	Result
Total cohort	25,333 patients
LVEF ≤40%	6,134 patients
LVEF >40%	19,199 patients
Mean age	70.9 ± 13.2 years
Men	54.7%
ACEi/ARB use, overall	40.7%
ARNI use, overall	15.1%
ACEi/ARB and ARNI use, LVEF ≤40%	35.9% and 39.7%, respectively
ACEi/ARB and ARNI use, LVEF >40%	42.2% and 7.3%, respectively
Primary outcome during follow-up	10,755 patients (42.5%) experienced all-cause mortality or first all-cause hospitalization
Female sex and ARNI use	Adjusted odds ratio 0.81 (95% CI 0.74–0.88), relative to male sex
Commercial insurance and ARNI use	Adjusted odds ratio 1.38 (95% CI 1.22–1.56), relative to Medicare
Medicaid and ARNI use	Adjusted odds ratio 0.63 (95% CI 0.53–0.75), relative to Medicare

Key Findings

The registry covers more than 275 outpatient clinics and 22 hospitals across Ohio and Florida. The index date is February 24, 2022, with outcomes assessed over 2 years.
ARNI use is associated with lower adjusted risk of death or hospitalization than ACEi/ARB overall (HR, 0.87; 95% CI, 0.82–0.93).
Among patients with LVEF >40%, the adjusted HR is 0.74 (95% CI, 0.66–0.83). Estimates are 0.77 (95% CI, 0.68–0.88) for LVEF >40% to <60% and 0.66 (95% CI, 0.49–0.90) for LVEF ≥60%.
No significant treatment-by-LVEF interaction is observed using continuous LVEF (P = .166), nor a treatment-by-sex interaction (P = .929).
A 1-year landmark analysis reassessing treatment yields consistent associations: adjusted HR, 0.89 (95% CI, 0.82–0.96) overall and 0.74 (95% CI, 0.64–0.84) for LVEF >40%.
Women have lower adjusted odds of ARNI use than men. Among patients with LVEF >40%, heart failure with improved EF is associated with higher odds of ARNI use (OR, 3.20; 95% CI, 2.83–3.62).

Clinical Implications

The findings extend observations from randomized trials into routine practice but do not establish causal benefit. The association at LVEF ≥60% requires caution: only 167 patients receive ARNI, confidence intervals are wide, and confounding by indication limits inference.

Additional limitations include prescription-based exposure rather than confirmed adherence, potential treatment changes, missing NT-proBNP and New York Heart Association functional class for risk stratification, and the absence of heart failure-specific hospitalization outcomes.

Conclusion

ARNI use is substantially lower above LVEF 40% and among women. It is associated with lower risk of all-cause death or first all-cause hospitalization across the studied LVEF spectrum. Prospective evaluation is needed to identify patients most likely to benefit, particularly at LVEF ≥60%.

Related Resources & Content

Angiotensin-neprilysin inhibition versus enalapril in heart failure — McMurray JJV, Packer M, Desai AS, et al.; The New England Journal of Medicine; 2014;371:993–1004.
Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction — Solomon SD, McMurray JJV, Anand IS, et al.; The New England Journal of Medicine; 2019;381:1609–1620.
Sacubitril/valsartan across the spectrum of ejection fraction in heart failure — Solomon SD, Vaduganathan M, Claggett BL, et al.; Circulation; 2020;141:352–361.
Angiotensin-neprilysin inhibition in patients with mildly reduced or preserved ejection fraction and worsening heart failure — Mentz RJ, Ward JH, Hernandez AF, et al.; Journal of the American College of Cardiology; 2023;82:1–12.
Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: A prespecified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF — Vaduganathan M, Mentz RJ, Claggett BL, et al.; European Heart Journal; 2023;44:2982–2993.
Management of heart failure with preserved ejection fraction: 2026 ACC Expert Consensus Decision Pathway — Kittleson MM, Panjrath GS, Bates K, et al.; Journal of the American College of Cardiology; published online July 2026.
Strategies for optimizing heart failure care in the older adult: A scientific statement from the American Heart Association — Lewsey SC, Martyn T, Blumer V, et al.; Circulation; 2026;154:e206–e230.