Sacubitril/Valsartan Versus Enalapril in Chagas Cardiomyopathy With Heart Failure With Reduced Ejection Fraction: A Systematic Review and Meta-Analysis

Chagas cardiomyopathy is a leading cause of heart failure (HF) with reduced ejection fraction (HFrEF) in endemic regions, yet patients with this distinct etiology have been underrepresented in pivotal HF trials. This creates significant uncertainty regarding the efficacy of guideline-directed therapies, including sacubitril-valsartan, in this population. PubMed, Cochrane (CENTRAL), Scopus, and Embase were searched from inception to December 17, 2025, for randomized controlled trials comparing sacubitril-valsartan to enalapril in patients with HFrEF due to Chagas cardiomyopathy. Primary outcomes were the composite endpoint of cardiovascular mortality or HF hospitalization, all-cause mortality, and individual components of the composite endpoint. Secondary outcomes included the percentage change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and adverse events. Three randomized controlled trials (n = 1225) patients were included. Sacubitril-valsartan did not significantly reduce the risk of the primary composite endpoint (risk ratio: 0.92; 95% confidence interval [CI]: 0.81–1.05; P = 0.216) or all-cause mortality (risk ratio: 0.96; 95% CI: 0.79–1.17; P = 0.691) compared to enalapril. However, it resulted in a significantly greater reduction in NT-proBNP levels (mean difference: −31.00%; 95% CI: −51.40 to −10.60; P < 0.01). The risks of renal dysfunction, symptomatic hypotension, and hyperkalemia were comparable between the 2 treatments. In patients with HFrEF due to Chagas cardiomyopathy, sacubitril-valsartan did not significantly improve hard clinical outcomes compared to enalapril but was associated with a substantially greater reduction in NT-proBNP and a similar safety profile. These findings underscore the unique pathophysiology of this disease and highlight the critical need for large, long-term outcome trials specifically powered for this neglected population.