Real-world comparative effectiveness of ARNI versus ACEi/ARB in HF with reduced or mildly reduced ejection fraction

AIMS: Sacubitril/valsartan is a first-in-class angiotensin receptor–neprilysin inhibitor (ARNI) with a class-1 guideline recommendation. We assessed the real-world effectiveness of ARNI versus angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) on all-cause and cardiovascular (CV)-related mortality and hospitalizations in heart failure (HF) with reduced or mildly reduced ejection fraction (EF). METHODS: Patient-level clinical, laboratory, drug dispensation, hospitalization, and mortality data were derived from the Swedish Heart Failure Registry (SwedeHF) and interlinked databases (1 April 2016–31 December 2020). Eligible ARNI:ACEi/ARB patients (n = 7275:24,604) had a left ventricular EF < 50%. Mortality and hospitalizations with ARNI (≤ 3 months pre-/post-1 April 2016 index [SwedeHF]; n = 1506) versus ACEi/ARB (≤ 3 months post-index; n = 17,108) were assessed using propensity score matching (1:1 ratio) with clinical variables, and sensitivity analysis (1:2/1:3 with, and 1:2 without clinical variables). RESULTS: ARNI induced a 23% reduction in all-cause mortality versus ACEi/ARB (1:1 hazard ratio [HR; 95% confidence interval (CI)]: 0.77 [0.63–0.95], p = 0.013), and a non-significant 23% relative risk reduction in CV-related mortality (0.77 [0.54–1.09], p = 0.13), but no difference in all-cause or CV-related hospitalization (1.02 [0.91–1.13]; p = 0.76; 1.01 [0.91–1.15]; p = 0.84, respectively). Sensitivity analyses confirmed all-cause mortality was reduced for ARNI versus ACEi/ARB (HR 0.90 [95% CI 0.82–0.99], p = 0.026), but not CV-related mortality (HR 1.04 [95% CI 0.89–1.22], p = 0.63). CONCLUSIONS: In this nationwide real-world study including a population of patients with HF with reduced or mildly reduced EF, ARNI as part of guideline-led Swedish clinical practice was associated with a statistically significant relative risk reduction in all-cause mortality compared with ACEi/ARB. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00392-022-02124-w.