Heart Failure Therapies Show Limited Impact in Chagas Disease

Guideline-recommended therapies for heart failure (HF) were found to be ineffective in patients with HF caused by Chagas disease regarding their clinical outcomes. However, researchers did observe a significant reduction in HF severity at 12 weeks, according to a new study published in JAMA. ¹

Chagas disease is caused by the parasite Trypanosoma cruzi (T. cruzi), which is spread through contact with triatomine bugs prevalent in rural areas of Mexico and Central and South America.² Nearly 10 million people are infected with Chagas disease worldwide, and an estimated 280,000 people are infected in the US—likely unknowingly. The disease typically occurs in 2 stages, the latter of which patients may be asymptomatic. The first stage happens immediately after infection, and adverse events may include fever, body aches, rash, or diarrhea, amongst others. The second stage, or chronic phase, can lead to severe complications, particularly related to cardiomyopathy.^1,2 The chronic phase occurs in 30% to 40% of patients who are infected and can present as chronic myocarditis, conduction system abnormalities, cardioembolic episodes, HF, and sudden death. ¹

There is limited evidence supporting the safety and efficacy of guideline-recommended medical therapies for patients with HF caused by Chagas disease. Patients with this condition are underrepresented in large randomized clinical trials for heart failure. Regardless, prior research has studied the efficacy of enalapril, an ACE inhibitor, for improving functional class and reducing heart size in patients with HF caused by Chagas disease. More recent studies have also shown enalapril can reduce myocardial fibrosis, which is why it was selected as a comparator for this open-label clinical trial PARACHUTE-HF (NCT04023227).¹

Inside the Study Design

The open-label trial assessed patients with heart failure with reduced ejection fraction (HFrEF) caused by Chagas disease from December 10, 2019, to September 13, 2023. Patients were randomized 1:1 to receive either the combination therapy sacubitril/valsartan or enalapril. Those in the sacubitril/valsartan group received treatment at 200 mg twice daily, and those in the enalapril group received treatment at 10 mg twice daily.

Patients included in the trial were aged 18 years or older and had at least 2 positive tests for T. cruzi. Patients were also required to have a left ventricular ejection fraction (LVEF) of 40% or less and a plasma level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) of 600 pg/mL or at least 400 pg/mL if they’d been hospitalized for HF in the previous 12 months.

The primary outcomes measured were time to cardiovascular death, time to first hospitalization for HF, and relative change in NT-proBNP concentration from baseline to 12 weeks.

Effectiveness of HF Guideline Therapy in Chagas Disease

There were 1840 patients initially screened for the clinical trial across sites in Brazil, Argentina, Colombia, and Mexico. Only 922 were included in the primary end point analysis; 462 were randomized to receive sacubitril/valsartan and 460 to receive enalapril with a median follow-up of 25.2 months.

The mean age of patients was 64.2 years; among them, 42% were female, and 54.4% self-identified as White. The mean LVEF was 29.8%, and the median NT-proBNP was 1730 pg/mL.

Death from cardiovascular causes occurred in 110 patients (23.8% [18.3% wins in the hierarchical comparison]) in the sacubitril/valsartan group and 117 (25.4% [17.5% wins]) in the enalapril group. The first hospitalization for HF occurred in 102 patients (22.1% [7.7% wins]) in the sacubitril/valsartan group and 111 (24.1% [6.9% wins]) in the enalapril group. Favorable relative change in the NT-proBNP concentration from baseline to 12 weeks was observed, with a median change of −30.6% (−54.3% to −0.9%) in the sacubitril/valsartan group (22.5% wins) and −5.5% (−31.9% to 37.5%) in those in the enalapril group (7.2% wins).

Serious adverse events, including death, were reported in 211 (45.7%) of patients in the sacubitril/valsartan group and 234 (50.9%) in the enalapril group. Symptomatic hypotension was the most common adverse event reported in 146 patients (31.6%) in the sacubitril/valsartan group and 126 (27.4%) in the enalapril group (rate ratio, 1.28 [95% CI, 0.96-1.70]).

There was no significant difference in death from cardiovascular causes of worsening HF when comparing outcomes between groups. However, researchers did observe a greater relative change in NT-proBNP concentration from baseline to 12 weeks in the sacubitril/valsartan group when compared with the enalapril group.

Understanding the Research Gap in Chagas Disease Care

Although Chagas disease is endemic to Latin America, it has begun to spread through the US and other European countries and is now considered endemic to the US.¹ The lack of evidence on HF therapy efficacy in patients with Chagas disease highlights gaps in inequitable research, as this disease impacts underrepresented populations.

High proportions of female individuals, Black patients, and patients with more advanced symptoms of HF are often underrepresented in research when compared with previous clinical trials measuring the impact of Chagas disease on HFrEF.

Similarly, this study was limited by its open-label design, potentially leading to more events in one group compared with the other. Follow-up NT-proBNP measurements were taken relatively early when compared with the other primary end points, as researchers were concerned about missing measurements due to sudden death. The findings were also not generalizable to patients with Chagas cardiomyopathy, including those with HF with mildly reduced ejection fraction or HF with preserved ejection fraction.

“Fully understanding the safety of HF treatments in this population is important, as these patients have more dysfunction of the right ventricle and lower blood pressure compared with other HF etiologies,” the study authors wrote.

References:

1. Lopes RD, Bocchie 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 3, 2025. doi:10.1001/jama.2025.19808

2. About Chagas disease. Centers for Disease Control and Prevention. September 4, 2024. Accessed December 3, 2025. https://www.cdc.gov/chagas/about/index.html