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Sacubitril/Valsartan vs Enalapril in Heart Failure Due to Chagas Disease: An Open-Label, Multicenter Randomized
Renato D Lopes1,2, Edimar Alcides Bocchi3, Luis Eduardo Echeverría4
1Duke Clinical Research Institute (DCRI), Duke Health, Durham, North Carolina.
Insights
Sacubitril/valsartan did not significantly improve clinical outcomes for heart failure patients with Chagas disease compared to enalapril. However, it led to a greater reduction in NT-proBNP levels at 12 weeks.
Area of Science:
- Cardiology
- Infectious Diseases
- Pharmacology
Background:
- Guideline-recommended heart failure (HF) treatments have uncertain efficacy and safety in Chagas disease patients.
- Chagas disease significantly impacts cardiac function, leading to heart failure with reduced ejection fraction (HFrEF).
Purpose of the Study:
- To evaluate the efficacy and safety of sacubitril/valsartan versus enalapril in patients with HFrEF caused by Chagas disease.
- To assess the impact of sacubitril/valsartan on cardiovascular death, HF hospitalization, and NT-proBNP levels.
Main Methods:
- A randomized trial involving 922 patients with HFrEF and Chagas disease across 83 sites in Latin America.
- Patients received either sacubitril/valsartan or enalapril, alongside standard therapy.
- The primary endpoint was a composite of cardiovascular death, HF hospitalization, or relative change in NT-proBNP at 12 weeks, analyzed using a win ratio approach.
Main Results:
- No significant difference in cardiovascular death or HF hospitalization rates between sacubitril/valsartan and enalapril groups.
- Sacubitril/valsartan demonstrated a significantly greater reduction in NT-proBNP levels at 12 weeks compared to enalapril (22.5% wins vs. 7.2% wins).
- The stratified win ratio favored sacubitril/valsartan (1.52; 95% CI, 1.28-1.82; P < .001) primarily due to NT-proBNP reduction.
Conclusions:
- Sacubitril/valsartan did not show a significant clinical benefit over enalapril for major adverse cardiovascular events in Chagas disease-related HFrEF.
- A notable reduction in NT-proBNP levels was observed with sacubitril/valsartan, suggesting a potential biomarker response.
- Further research is needed to clarify the long-term clinical implications of NT-proBNP reduction in this specific patient population.
Importance:
The efficacy and safety of guideline-recommended treatments for heart failure (HF) are uncertain in patients with Chagas disease.
Objective:
To evaluate the efficacy and safety of the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan in patients with HF with reduced ejection fraction due to Chagas disease.
Design, Setting, And Participants:
From December 10, 2019, through September 13, 2023, patients with HF, confirmed diagnosis of Chagas disease, left ventricular ejection fraction of 40% or less, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) of 600 pg/mL or greater (or B-type natriuretic peptide [BNP] ≥150 pg/mL) or 400 pg/mL or greater (or BNP ≥100 pg/mL) if hospitalized for HF within the previous 12 months were screened at 83 sites in Argentina, Brazil, Colombia, and Mexico. Statistical analysis was conducted between May and July 2025.
Interventions:
Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or enalapril (target dose, 10 mg twice daily), in addition to standard therapy.
Main Outcomes And Measures:
The primary end point was a hierarchical composite outcome tested, in order, of death from cardiovascular causes, hospitalization for HF, or relative change in NT-proBNP from baseline to 12 weeks. The primary analysis was done using a win ratio approach.
Results:
Overall, 462 participants were randomized to receive sacubitril/valsartan and 460 to receive enalapril (mean [SD] age, 64.2 [10.8] years; 387 [42.0%] were female). Over a median (IQR) follow-up of 25.2 (18.4-33.2) months, cardiovascular death occurred in 110 patients (23.8% [18.3% wins in the hierarchical comparison]) in the sacubitril/valsartan group and 117 patients (25.4% [17.5% wins]) in the enalapril group. A total of 102 patients (22.1% [7.7% wins]) in the sacubitril/valsartan group and 111 (24.1% [6.9% wins]) in the enalapril group experienced a first hospitalization for HF. Patients in the sacubitril/valsartan group had a median (IQR) decrease in NT-proBNP of 30.6% (-54.3% to -0.9%) at 12 weeks, leading to 22.5% wins, while those in the enalapril group had a 5.5% (-31.9% to 37.5%) decrease (7.2% wins). The resulting stratified win ratio was 1.52 (95% CI, 1.28-1.82; P < .001) for sacubitril/valsartan compared with enalapril.
Conclusions And Relevance:
In patients with HF with reduced ejection fraction due to Chagas disease, there was no significant difference in clinical outcomes between sacubitril/valsartan and enalapril, but there was a greater reduction in NT-proBNP at 12 weeks in patients in the sacubitril/valsartan group.
Trial Registration:
ClinicalTrials.gov Identifier: NCT04023227.
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