Angiotensin Receptor-Neprilysin Inhibitors and Mortality Among Patients With HFrEF.

While trial evidence supports the benefit of angiotensin receptor-neprilysin inhibitor (ARNI) therapy in heart failure with reduced ejection fraction (HFrEF), its effectiveness in routine clinical practice is less explored. This study investigated the relative and absolute effectiveness of ARNI in patients with HFrEF. This nationwide Danish database study included patients with left ventricular ejection fraction (LVEF) ≤40%, 2018 to 2023. Using a prevalent new user design, 2,446 ARNI initiators were matched 1:2 to 4,892 users of angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) based on propensity scores, age, LVEF, and NT-proBNP. The primary outcome was all-cause mortality; secondary outcomes were cardiovascular mortality and hospitalization. There were 279 deaths among ARNI initiators (5.6/100 person-years) and 533 among ACE-I/ARB users (6.7/100 person-years), yielding a hazard ratio (HR) of 0.85 (95% CI, 0.74 to 0.98) for all-cause mortality. A significant interaction was observed for recent hospitalization (p = 0.04), with ARNI yielding a lower HR in this group. HRs were otherwise consistent across age, sex, LVEF, NT-proBNP, NYHA class, ischemic heart disease, chronic kidney disease, and type 2 diabetes. The largest absolute mortality reductions were seen in subgroups with recent hospitalization, NYHA class III to IV, and severely elevated NT-proBNP. ARNI was also associated with a lower risk of cardiovascular death (HR, 0.81; 95% CI, 0.65 to 0.99), but not with other secondary outcomes. In this study, ARNI was associated with a 15% reduction in all-cause mortality vs ACE-I/ARB. Patients with advanced or symptomatic heart failure appeared to experience the greatest absolute benefit.