The PARACHUTE-HF trial has delivered groundbreaking results for patients with heart failure caused by Chagas disease, demonstrating that sacubitril/valsartan significantly outperforms enalapril in this previously understudied population. The findings, presented at ESC Congress 2025, represent the first prospective randomized trial specifically designed to evaluate heart failure treatments in patients with chronic Chagas cardiomyopathy.
Trial Design and Patient Population
PARACHUTE-HF was an academic-led, open-label, blinded-endpoint adjudication trial conducted across more than 80 sites in Brazil, Argentina, Mexico, and Colombia. The study randomized 922 patients with confirmed Chagas disease and heart failure, with participants having a mean age of 64 years and 42% being women. The mean left ventricular ejection fraction was 29.8%, and 44.4% had experienced prior hospitalization for heart failure.
Eligibility criteria included diagnosis of Chagas disease confirmed by at least two different serological tests positive for Trypanosoma cruzi infection, left ventricular ejection fraction ≤40%, New York Heart Association functional class II to IV symptoms, and NT-proBNP ≥600 pg/ml or ≥400 pg/ml with hospitalization for heart failure within the last 12 months.
Primary Endpoint Results
Patients were randomized 1:1 to receive either sacubitril/valsartan (50 or 100 mg twice daily titrated to a target of 200 mg twice daily) or enalapril (2.5 or 5 mg twice daily titrated to a target of 10 mg twice daily). The primary endpoint was a hierarchical composite outcome consisting of cardiovascular death, first hospitalization for heart failure, and the relative change from baseline to week 12 in NT-proBNP, analyzed using a win ratio approach.
Sacubitril/valsartan demonstrated a 52% higher likelihood of achieving a better primary outcome compared with enalapril (stratified unmatched win ratio 1.52; 95% confidence interval 1.28 to 1.82; p<0.001). Over a median follow-up of 25 months, rates were similar for cardiovascular death (hazard ratio 0.95; 95% CI 0.73 to 1.23) and first heart failure hospitalization (hazard ratio 0.92; 95% CI 0.70 to 1.20) between the two treatment groups.
Biomarker-Driven Efficacy
The significant difference in the primary outcome was predominantly driven by the percent change in NT-proBNP from baseline to 12 weeks. The logarithmic median change from baseline was -30.6% in patients assigned to sacubitril-valsartan compared to -5.5% in those assigned to enalapril (ratio of adjusted geometric mean change 0.68; 95% CI 0.62 to 0.75), representing a 32% reduction in NT-proBNP levels.
Safety Profile
The safety profiles of both treatments were comparable, with discontinuations due to adverse events occurring in 6.1% of patients receiving sacubitril/valsartan and 9.8% of those receiving enalapril.
Clinical Significance for Neglected Disease
"Heart failure caused by Chagas disease has unique clinical features with worse prognosis than other causes of heart failure despite the fact that patients are often younger and have fewer comorbidities," explained Professor Renato Lopes from Duke University Medical Center, the trial's Principal Investigator. "There have been no prospective randomised trials testing the effects of standard treatments in patients with Chagas disease and heart failure."
Chagas disease, caused by Trypanosoma cruzi infection, affects more than 7 million people primarily from Latin America. The parasites are mainly transmitted by contact with feces/urine of infected triatomine bugs, but can also spread through contaminated food/beverages, during pregnancy or birth, through blood/blood products, organ transplantation, and laboratory accidents. The disease is spreading globally due to migration of infected patients to North America, Europe, Asia, and Australia.
Chagas cardiomyopathy is considered the most common and serious manifestation of chronic Chagas disease, occurring in 30-40% of infected people during long-term follow-up.
Global Health Impact
"Our study provides the first randomized trial evidence to support a pharmacological treatment specifically in this high-risk population," Professor Lopes concluded. "PARACHUTE-HF shows that much-needed studies to better characterize chronic Chagas cardiomyopathy and to define the benefit/risk of new therapies in this condition are possible. The PARACHUTE-HF trial provides a successful model for international collaborations with the shared goal of evaluating the impact of new therapies on cardiovascular outcomes in patients with neglected diseases."
