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

Abstract

Background and Purpose: Heart failure with reduced ejection fraction (HFrEF) continues to cause significant global morbidity and mortality. With sacubitril/valsartan now recommended as first-line therapy in guidelines, this review aimed to evaluate its safety and efficacy compared to enalapril in HFrEF patients.

Methodology: We systematically searched PubMed, Scopus, Ovid, Cochrane Library, and ProQuest databases through December 2024. Eligible studies were randomized controlled trials (RCTs) or observational studies comparing sacubitril/valsartan versus enalapril among patients diagnosed with HFrEF. The risk ratios (RR) and mean differences (MDs) with 95% confidence interval (CI) were computed and p-value < 0.05 was considered as a level of significance. Statistical analyses were performed using RevMan.

Results and Discussions: This study included 10 RCTs and 2 prospective cohort studies with 11,765 patients. 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 result robustness and resolved heterogeneity in outcomes. These findings indicate that sacubitril/valsartan improves survival, quality of life, and biomarkers in HFrEF, consistent with guideline recommendations for early use. The higher risk of hypotension underscores the importance of careful patient selection and monitoring, but the overall safety profile remains comparable to enalapril, supporting sacubitril/valsartan as a more effective option.

Conclusions: 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.