Sacubitril/Valsartan Shows No Clinical Advantage over enalapril in HF due to Chagas disease: JAMA

This multicenter, double-blind, randomized clinical trial enrolled patients from 83 sites in Argentina, Brazil, Colombia, and Mexico. Participants were screened from December 10, 2019, to September 13, 2023. Eligible adults had confirmed Chagas disease, HF with left ventricular ejection fraction ≤40%, and elevated natriuretic peptides (NT-proBNP ≥600 pg/mL or BNP ≥150 pg/mL; thresholds lowered to 400 pg/mL or BNP ≥100 pg/mL if recently hospitalized for HF). Of 922 participants who met eligibility criteria and were randomized, 462 received sacubitril/valsartan and 460 received enalapril; target doses were 200 mg twice daily for sacubitril/valsartan and 10 mg twice daily for enalapril, given with guideline-directed therapy. The primary composite outcome of cardiovascular death, HF hospitalization, and NT-proBNP reduction at 12 weeks was tested in a hierarchical win-ratio approach. Statistical analyses were performed between May and July 2025, with a median follow-up time of 25.2 months.

Results

• Baseline demographics were well matched: mean age was 64.2 years, and 42% of participants were female.

• Over the median follow-up of 25.2 months, the sacubitril/valsartan group had 110 cardiovascular deaths (23.8%, corresponding to 18.3% wins in hierarchical comparison), whereas the enalapril group had 117 deaths (25.4%, 17.5% wins).

• First HF hospitalizations occurred in 102 patients (22.1%, 7.7% wins) receiving sacubitril/valsartan and 111 (24.1%, 6.9% wins) receiving enalapril.

• At 12 weeks, sacubitril/valsartan demonstrated a markedly greater NT-proBNP reduction, with a median decrease of 30.6% (IQR −54.3% to −0.9%) representing 22.5% wins.

• The enalapril group had a median 5.5% decrease (IQR −31.9% to 37.5%) and 7.2% wins.

• Overall, the stratified win ratio favored sacubitril/valsartan at 1.52 (95% CI 1.28–1.82; P < 0.001). Despite this biomarker improvement, no meaningful difference emerged in the hard clinical outcomes of cardiovascular death or HF hospitalization.

Among patients with HFrEF with Chagas disease, sacubitril/valsartan did not demonstrate any clinically important benefit over enalapril despite achieving substantially larger reductions in NT-proBNP at 12 weeks.

Reference:

Lopes RD, Bocchi EA, Echeverría LE, et al. Sacubitril/Valsartan vs Enalapril in Heart Failure Due to Chagas Disease: An Open-Label, Multicenter Randomized Clinical Trial. JAMA. Published online December 03, 2025. doi:10.1001/jama.2025.19808