Chagas disease, caused by Trypanosoma cruzi, is a leading cause of non-ischemic cardiomyopathy in Latin America, affecting 6–7 million people. Despite clear benefit of sacubitril/valsartan over enalapril in HFrEF of other etiologies (PARADIGM-HF trial), its efficacy in Chagas cardiomyopathy remained unknown due to distinct pathophysiology involving chronic inflammation, fibrosis, and microvascular dysfunction.
The PARACHUTE-HF trial (Prospective Evaluation of ARNI in Patients with Chagas Heart Failure) was a multicenter, double-blind, active-controlled phase 3 study conducted in Brazil, Argentina, and Colombia. Adults with symptomatic HFrEF (LVEF ≤40%) secondary to chronic Chagas disease, elevated NT-proBNP (≥600 pg/mL or ≥400 pg/mL if hospitalized within 12 months), and on stable guideline-directed therapy were randomized 1:1 to sacubitril/valsartan (target 97/103 mg twice daily) or enalapril (target 10 mg twice daily).
The primary endpoint was the ratio of baseline to 12-week NT-proBNP (analyzed on log scale). Secondary endpoints included change in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, 6-minute walk distance, NYHA class, and safety. Between 2019 and 2023, 200 patients were randomized (mean age 60 years, 37% women, mean LVEF 31%, median NT-proBNP 1700 pg/mL). At 12 weeks, the geometric mean NT-proBNP decreased substantially in both arms, but the between-group ratio was 0.96 (95% CI 0.75-1.22; p=0.72), demonstrating no superiority of sacubitril/valsartan. No significant differences were observed in KCCQ score (+6.3 vs +5.8 points), 6-minute walk distance, or NYHA class improvement. Clinical composite outcomes and hospitalization rates were similar.
Adverse events occurred at comparable frequency, though symptomatic hypotension was numerically higher with sacubitril/valsartan (14% vs 8%). Hyperkalemia and renal worsening were infrequent in both groups. In conclusion, among patients with heart failure due to Chagas disease, sacubitril/valsartan did not provide incremental NT-proBNP reduction or clinical benefit compared with enalapril at 12 weeks. These neutral results contrast sharply with the 20% relative risk reduction seen in PARADIGM-HF and suggest that chronic parasitic myocardial injury may attenuate the neurohormonal response to neprilysin inhibition. Longer-term studies are needed to determine whether these findings extend to hard clinical outcomes in this population.
Link: https://jamanetwork.com/journals/jama/article-abstract/2842279
