Sacubitril-Valsartan vs Enalapril in Heart Failure Due to Chagas Disease: Primary Results of ANSWER-HF Randomized Trial.

BACKGROUND

Chronic Chagas cardiomyopathy (CCC) represents a common cause of nonischemic heart failure with reduced ejection fraction (HFrEF) in Latin America, yet evidence from randomized trials remains scarce. Sacubitril-valsartan has shown benefits in HFrEF of other etiologies, but less is known about its effects on CCC.

OBJECTIVES

The authors sought to compare the effects of sacubitril-valsartan vs enalapril on cardiac remodeling, functional outcomes, biomarkers, and safety in patients with CCC and HFrEF.

METHODS

ANSWER-HF was a randomized, double-blind, controlled trial in Brazil. A total of 190 patients with CCC and HFrEF (left ventricular ejection fraction [LVEF] <40%, NYHA functional class II-IV) were randomized in a 1:1 ratio to sacubitril-valsartan or enalapril and followed for 6 months. The primary endpoint was change in LVEF from baseline to 6 months. The win ratio method analyzed the hierarchical secondary endpoint of cardiovascular death, heart failure hospitalization, N-terminal pro-B-type natriuretic (NT-proBNP) change, and LVEF change.

RESULTS

Mean age was 61 years, 40% women, and 69% Black or mixed race. Baseline mean LVEF was 30.1%. At 6 months, mean LVEF increased by 2.1% with sacubitril-valsartan and 1.2% with enalapril (between-group difference 0.9 percentage points; 95% CI: -0.9 to 2.6; P = 0.36). In hierarchical analysis, sacubitril-valsartan achieved more wins than enalapril (win ratio 1.80; 95% CI: 1.27-2.63). Median NT-proBNP was significantly lower with sacubitril-valsartan (geometric mean ratio 0.68; 95% CI: 0.57-0.81; P < 0.001). No significant differences were observed in echocardiographic remodeling or 6-minute walk distance, and the occurrence of safety outcomes were comparable.

CONCLUSIONS

In patients with CCC and HFrEF, sacubitril-valsartan did not result in significant improvements in LVEF compared with enalapril after 6 months, but was associated with a greater reduction in NT-proBNP. No safety concerns were associated with either the sacubitril-valsartan or enalapril group. These findings establish the feasibility and safety of conducting trials in this neglected disease, demonstrate biological activity of sacubitril-valsartan and enalapril in HFrEF due to CCC, and chart the path for larger, outcome-driven studies. The ANSWER-HF represents an important step forward, beginning a new era of evidence generation for Chagas cardiomyopathy. (Angiotensin Receptor-Neprilysin Inhibition in Chagas Cardiomyopathy With Reduced Ejection Fraction [ANSWER-HF]; NCT04853758).