Key Points:
- Chronic Chagas cardiomyopathy (CCC) patients are underrepresented in heart failure (HF) trials and have a worse prognosis than other etiologies
- The PARACHUTE-HF trial was the first randomized, phase IV study evaluating sacubitril-valsartan versus enalapril in patients with chronic Chagas cardiomyopathy (CCC) and heart failure with reduced ejection fraction (HFrEF) among over 900 patients across 100 sites in Latin America
- The study found ARNI was significantly favored over enalapril in a primary hierarchical composite outcome of time to cardiovascular death, first heart failure hospitalization, or relative change in NT-proBNP at 12 weeks (stratified win ratio 1.52; 95% CI 1.28-1.82; p < 0.001)
- The investigators concluded that this was the first randomized trial supporting specific pharmacologic therapy in a unique high-risk cohort (CCC patients), with need for future studies to better understand and treat such patients
Chronic Chagas cardiomyopathy (CCC), a severe form of heart failure (HF) resulting from Trypanosoma cruzi infection, affects millions, primarily in Latin America, but also increasingly in regions like North America and Europe due to migration. This condition carries a worse prognosis despite often affecting younger individuals with fewer comorbidities. Notably, patients with Chagas-related HF have been underrepresented in landmark HFrEF trials. PARACHUTE-HF is the first randomized study evaluating guideline-directed medical therapy (GDMT, specifically ARNI vs ACE inhibitor) in this population.
PARACHUTE-HF was an academic-led, open-label, randomized, blinded-endpoint adjudication trial conducted at over 80 sites across Brazil, Argentina, Mexico, and Colombia. A total of 922 patients with confirmed Chagas infection (by two positive serologies), LVEF ≤40%, NYHA II-IV symptoms, and elevated NT-proBNP (or recent HF hospitalization) were randomized 1:1 to sacubitril/valsartan (titrated to 200 mg BID) or enalapril (titrated to 10 mg BID). The primary outcome was a hierarchical composite – cardiovascular death, first HF hospitalization, and relative change in NT-proBNP at 12 weeks – analyzed via the win ratio approach.
Sacubitril/valsartan demonstrated a 52% higher likelihood of a superior outcome versus enalapril (win ratio 1.52; 95% CI, 1.28–1.82; p < 0.001). This benefit was primarily due to significantly greater NT-proBNP reduction: a logarithmic median drop of -30.6% vs -5.5%, translating to an adjusted geometric mean change ratio of 0.68 (95% CI, 0.62–0.75). Over a median follow-up of 25 months, rates of cardiovascular death (HR 0.95; 95% CI, 0.73–1.23) and first HF hospitalization (HR 0.92; 95% CI, 0.70–1.20) were comparable between groups. Discontinuation due to adverse events occurred in 6.1% for ARNI and 9.8% for enalapril; both appeared similarly well tolerated.
PARACHUTE-HF marks a milestone in Chagas-related HF research, demonstrating that sacubitril/valsartan results in superior biomarker improvements compared to enalapril in a previously neglected disease context. Although the trial wasn’t powered for mortality or hospitalization endpoints, the substantial NT-proBNP reduction, an established prognostic marker, suggests meaningful clinical potential. The trial also serves as a successful model for international collaboration addressing neglected cardiovascular diseases. This is best summarized by Principal Investigator Renato Lopes, MD, PhD: “Our study provides the first randomized trial evidence to support a pharmacological treatment specifically in this high-risk population. 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.”