Cardiorenal safety and efficacy of angiotensin receptor‑neprilysin inhibitors in heart failure across the ejection fraction spectrum: A meta‑analysis and meta‑regression of RCTs with 28,001 patients

Angiotensin receptor-neprilysin inhibitors (ARNIs), including sacubitril/valsartan, exert blood pressure-lowering and organ-protective effects in patients with heart failure (HF). However, differences of these effects across HF phenotypes and their impact on renal outcomes remain unclear. The present systematic review aimed to evaluate the antihypertensive efficacy, safety and cardiorenal benefits of ARNIs vs. angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) in patients with HF with reduced, mildly reduced, and preserved ejection fractions. Data were extracted from PubMed, Scopus, Cochrane, ProQuest and Google Scholar up to July 2025. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Meta-analyses were performed using risk ratios (RRs) with 95% confidence intervals (CIs). Data analyses were conducted using RevMan version 5.4 and STATA version 16.0. Outcomes encompassed all-cause mortality, cardiovascular mortality, HF-related hospitalization, major adverse cardiovascular events (MACEs) and adverse events. A total of 18 randomized control trials involving 28,001 patients were included. Compared with ACE-I/ARB, ARNI decreased all-cause (RR=0.67; 95% CI=0.83-0.97) and cardiovascular mortality (RR=0.84; 95% CI=0.77-0.92), HF hospitalization (RR=0.87; 95% CI=0.81-0.93) and MACE (RR=0.89; 95% CI=0.85-0.94), but increased symptomatic hypotension (RR=1.54; 95% CI=1.43-1.65). Subgroup analysis by left ventricular ejection fraction category did not reveal any significant effect modification across outcomes. Meta-regression identified N-terminal prohormone of brain natriuretic peptide (P=0.02) and body mass index (P<0.0001) as predictors of cardiovascular mortality. Estimated glomerular filtration rate was associated with all-cause mortality (P=0.001) and hypotension (P=0.03), while sex (P=0.001) predicted hospitalization. Systolic blood pressure (P=0.001) was linked to renal outcomes. Overall, ARNIs confer consistent cardiorenal benefits across the HF spectrum, particularly in patients with elevated systolic blood pressure and decreased renal function, though hypotension requires careful monitoring. The present study was registered in PROSPERO (registration no. CRD42024569374).