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

Objective:

To compare real-world outcomes associated with sacubitril/valsartan, an angiotensin receptor/neprilysin inhibitor (ARNI), versus ACE inhibitor or angiotensin receptor blocker (ACEi/ARB) therapy across left ventricular ejection fraction (LVEF) levels.

Approach:

Design and population: Retrospective electronic health record cohort of 25,333 adults with heart failure from more than 275 outpatient clinics and 22 hospitals across Ohio and Florida.
Exposure and outcome: Baseline renin-angiotensin-aldosterone system therapy is classified as ARNI, ACEi/ARB, or none. The primary outcome is all-cause death or first all-cause hospitalization over 2 years.
Analysis: Adjusted Cox models compare ARNI with ACEi/ARB overall and across prespecified LVEF strata. A 1-year landmark sensitivity analysis reassesses treatment among patients alive at 1 year and evaluates subsequent outcomes.

Key Findings:

ARNI is associated with lower risk of death or hospitalization than ACEi/ARB overall (adjusted 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), with estimates of 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).
Landmark findings are consistent with the primary analysis: 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.

Interpretation:

ARNI use is associated with lower risk of death or hospitalization across the studied LVEF range. The association at LVEF ≥60% is hypothesis-generating and does not establish efficacy beyond populations with demonstrated randomized benefit.

Limitations:

The retrospective, nonrandomized design is susceptible to residual confounding and confounding by indication.
Prescription records do not establish adherence, and treatment may change during follow-up.
NT-proBNP and New York Heart Association functional class are unavailable for risk stratification; heart failure-specific hospitalization outcomes are not assessed.
Only 167 patients with LVEF ≥60% receive ARNI, limiting precision in this subgroup.

Conclusion:

ARNI use is associated with lower risk of all-cause death or first all-cause hospitalization than ACEi/ARB across the LVEF spectrum. Prospective evaluation is needed to identify patients most likely to benefit, particularly at LVEF ≥60%.