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

At a Glance

Key Highlights

• The cohort includes 25,333 patients; 10,755 (42.5%) experience all-cause death or first all-cause hospitalization during 2 years of follow-up.

• ARNI use is associated with lower adjusted risk of the primary outcome than ACEi/ARB use 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). The 1-year landmark analysis yields a consistent estimate (HR, 0.74; 95% CI, 0.64–0.84).

• No significant treatment-by-LVEF interaction is observed with continuous LVEF modeling (P = .166), nor a treatment-by-sex interaction (P = .929).

• Findings at LVEF ≥60% are hypothesis-generating because ARNI use is uncommon, confidence intervals are wide, and confounding by indication limits interpretation.

Guideline-Based Recommendations

Diagnosis

• Study eligibility requires a heart failure encounter in the preceding 12 months and available LVEF and eGFR measurements. These are cohort criteria rather than diagnostic recommendations.

Management

• The study compares baseline ARNI with ACEi/ARB treatment and does not establish causal benefit.

• The article cites contemporary guidance supporting sacubitril/valsartan in selected patients with heart failure with preserved EF, particularly women and those with LVEF below approximately 55%–60%.

Monitoring & Follow-up

• The primary outcome is all-cause mortality or first all-cause hospitalization over 2 years.

• In the 1-year landmark analysis, therapy is reassessed among patients alive at 1 year, treatment status is reclassified, and subsequent outcomes are evaluated. The study does not establish a clinical monitoring schedule.

Risks

• The retrospective, nonrandomized design is susceptible to residual confounding and confounding by indication.

• Prescription status does not establish adherence, and treatment may change during follow-up.

• NT-proBNP and New York Heart Association functional class are unavailable for risk stratification, and heart failure-specific hospitalization outcomes are not assessed.

• Only 167 patients with LVEF ≥60% receive ARNI, limiting precision.

Patient & Prescribing Data

Mean age is 70.9 years, and 54.7% of participants are men. Overall, 15.1% receive ARNI and 40.7% receive ACEi/ARB. ARNI use is 39.7% among patients with LVEF ≤40% and 7.3% among those with LVEF >40%.

Among patients receiving ARNI or ACEi/ARB, women have lower adjusted odds of ARNI use than men (OR, 0.81; 95% CI, 0.74–0.88). Compared with Medicare, Medicaid is associated with lower odds of ARNI use, whereas commercial insurance is associated with higher odds.

Clinical Best Practices

• Interpret treatment associations within the limitations of the observational design.

• Treat the LVEF ≥60% finding as hypothesis-generating rather than evidence establishing efficacy beyond populations with demonstrated randomized benefit.

• Distinguish utilization differences by sex and insurance from treatment recommendations. Prospective evaluation is needed to identify patients most likely to benefit.

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.