Efficacy and Safety of Sacubitril/Valsartan Versus Enalapril in the Treatment of Heart Failure With Reduced Ejection Fraction: A Systematic Review and Meta-Analysis

Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of cardiovascular morbidity and mortality worldwide. The aim of this systematic review and meta-analysis was to evaluate the safety and efficacy of sacubitril/valsartan compared to enalapril in patients with HFrEF. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. We systematically searched PubMed, Scopus, Ovid, Cochrane Library, and ProQuest databases from inception to December 23, 2024. Eligible studies were randomized controlled trials (RCTs) or observational studies published in English, comparing sacubitril/valsartan versus enalapril among adult patients diagnosed with HFrEF. The risk ratios (RRs) and mean differences (MDs) with 95% confidence interval (CI) were computed, and p < 0.05 was considered as a level of significance. Statistical analyses were performed using RevMan (Cochrane Collaboration, London, UK). This study included 10 RCTs and two prospective cohort studies with 11,765 patients (5,879 in the sacubitril/valsartan group and 5,886 in the enalapril group, 45.26 to 69.0 years of age). Sacubitril/valsartan significantly reduced all-cause mortality (RR = 0.85, P = 0.0006), cardiovascular mortality (RR = 0.81, P < 0.0001), and heart failure rehospitalization (RR = 0.68, P = 0.006) compared to enalapril. Hypotension was more frequent with sacubitril/valsartan (RR = 1.54, P < 0.00001), while no significant differences were found for hyperkalemia, angioedema, worsening renal function, or left ventricular ejection fraction (LVEF). Sacubitril/valsartan was associated with lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (MD = -427.50, P = 0.009) and better Kansas City Cardiomyopathy Questionnaire (KCCQ) scores (MD = 1.64, P < 0.00001). Sensitivity analyses confirmed robustness and resolved heterogeneity in several outcomes. Publication bias could not be assessed due to the small number of studies (<10), as funnel plot asymmetry and related tests are unreliable with limited studies. This limitation should be considered when interpreting the results, as undetected publication bias remains possible. Sacubitril/valsartan demonstrates superior efficacy over enalapril in key clinical and patient-reported outcomes. Further research is needed to investigate its long-term safety and effectiveness across diverse patient populations.