The combination of sacubitril and valsartan appeared superior to enalapril in the first randomized trial to generate high-quality evidence to support a drug treatment specifically for patients with heart failure caused by Chagas disease.

But the results from the trial PARACHUTE-HF were driven by reductions in levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), one component of the primary composite endpoint. Researchers noted only small, nonsignificant reductions in the primary endpoint’s harder clinical outcomes, including cardiovascular death and hospitalization for heart failure.

Even so, the data may help move the needle on treatment for the disease, according to lead investigator Renato Lopes, MD, of Duke University in Durham, North Carolina.

“I think now we have higher-quality evidence that supports one specific treatment, not necessarily to make a class 1A recommendation in the guidelines, but clearly this is a first step in the right direction,” Lopes said. 

“There is a need for more rigorously conducted clinical trials in Chagas disease to better define the cardiovascular benefit-risk profile of new treatment options for this neglected and high-risk population,” he added. 

Lopes presented the PARACHUTE-HF trial at the European Society of Cardiology (ESC) Congress 2025. 

No Evidence-Based Treatments 

Chagas cardiomyopathy is a chronic inflammatory condition caused by infection with the Trypanosoma cruzi parasite. Estimates suggest about 6 million people are affected worldwide, mostly in Central and South America, and approximately 300,000 patients are living with Chagas disease in the US, according to data from The Lancet cited during the PARACHUTE-HF presentation.

Severe cases of Chagas cardiomyopathy led to overt heart failure, ventricular arrhythmias, thromboembolic events, and sudden cardiac death. The prognosis is poor compared with other cardiomyopathies, according to Scott Solomon, MD, of Harvard Medical School, Boston, who served as a discussant for the study.

Lopes said heart failure is one of the most common complications of patients with Chagas disease, and patients with Chagas-related heart failure have higher rates of hospitalization and mortality than other patients with heart failure. As yet, no clinical trial evidence to guide treatment is available.

PARACHUTE-HF was a randomized, open-label study with blinded endpoint adjudication designed to evaluate the effect of sacubitril/valsartan compared with enalapril in patients with heart failure with reduced ejection fraction caused by Chagas disease.

The trial enrolled 922 patients from Central or South America who were randomly assigned to sacubitril/valsartan at a target dose of 200 mg twice daily or enalapril at a target dose of 10 mg twice daily. Patients were followed up until 302 primary outcomes occurred. 

The trial used a win ratio design with a hierarchical primary endpoint of time to cardiovascular death, time to first heart failure hospitalization, and relative change in NT-proBNP from baseline to week 12.

For each pair comparison, researchers evaluated time to cardiovascular death, and if there was no winner, they considered time to first heart failure hospitalization. If no winner emerged, they recorded the relative change in NT-proBNP. A win required the ratio of week 12 to baseline to differ by at least 20% between the two participants.

Secondary endpoints included classic cardiovascular death or heart failure hospitalization. 

Baseline characteristics were very balanced between the study groups. The mean age was 64 years, 42% were women, 15% were Black, and the mean ejection fraction was 30%. Two thirds of the patients had New York Heart Association class II heart failure, and a third had class III heart failure. Mean NT-proBNP levels at baseline were around 1700 pg/mL, and around 45% of patients had a prior hospitalization due to heart failure.

Patients were well treated at baseline, with 80% on an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, 90% on a beta blocker, 73% on a mineralocorticoid antagonist, and 70% on a diuretic.

The researchers made 212,520 comparisons by pairing participants from each group. Results showed 48.5% overall wins for sacubitril/valsartan vs 31.6% for enalapril, which translated to a significant win ratio of 1.52 (95% CI, 1.28-1.82) for sacubitril/valsartan.

The result was driven by a reduction in NT-proBNP levels, with a win difference of 15.3%, whereas the first two components of the endpoint only marginally favored sacubitril/valsartan. Both showed win differences of 0.8%. 

The researchers observed a nonsignificant 5% reduction in the relative risk for cardiovascular death with sacubitril/valsartan and an 8% reduction in relative risk in heart failure hospitalization, which was also nonsignificant.

The main difference between the two groups was a large and significant reduction in NT-proBNP levels in the sacubitril/valsartan vs enalapril group (-30.6 pg/mL vs -5.5 pg/mL). 

Putting PARACHUTE-HF in Context

The results of PARACHUTE-HF reported at ESC may provide evidence of benefit, but some experts expressed concern when the details of the trial’s rationale and design were published in JACC: Heart Failure in 2024.

In “A Letter to the Editor of JACC-HF, which was Rejected,” published on the Substack Sensible Medicine, Anis Rassi, Jr, MD, PhD, and colleagues criticized the decision to use the maximum dose of 200 mg twice daily for sacubitril/valsartan but only half the maximum dose of 40 mg daily for enalapril. They noted this difference was particularly questionable given the use of a win ratio analysis that included NT-proBNP levels, which are dependent on dose with enalapril.

“The key question remains: Are the observed differences due to the addition of sacubitril to vasodilation therapy or merely a result of unequal dosing?” they wrote. 

Rassi, of the Division of Cardiology at Hospital do Coração Anis Rassi, Goiania, Brazil, and colleagues also cited the study’s open-label design and potential conflicts of interest with the trial’s sponsor as problematic.

Despite this criticism, Solomon, who was involved in the PARADIGM-HF trial, said PARACHUTE-HF was an important trial during a discussion of the findings.

PARADIGM-HF showed sacubitril/valsartan significantly reduced cardiovascular death or heart failure hospitalization by 20% in patients with heart failure. The trial included 8442 patients, 113 of whom had Chagas cardiomyopathy, and although the numbers were very small, results suggested that the benefit in the main trial may also have occurred in the patients with Chagas disease, according to Solomon. 

He suggested the PARACHUTE-HF results were not inconsistent with those of PARADIGM-HF.

“PARACHUTE-HF was a much smaller trial, but the event rates were much higher than in PARADIGM-HF. While PARACHUTE was underpowered for the hard endpoints, the confidence intervals include the PARADIGM point estimate; the reduction in NT-proBNP seen in PARACHUTE of about 30% was similar to that seen in the PARADIGM-HF trial, and sacubitril/valsartan appeared to be safe in Chagas disease,” Solomon said. 

“Virtually every guideline-directed medical therapy for heart failure with reduced ejection fraction works regardless of heart failure etiology, and it is unlikely that Chagas cardiomyopathy behaves very differently,” he said. 

“While larger randomized trials would certainly inform the community, in the absence of more data, I believe that the use of sacubitril/valsartan in cardiomyopathy appears safe, well tolerated, and likely effective,” Solomon said. 

The PARACHUTE-HF trial was funded by Novartis. Lopes reported receiving consulting fees/honoraria from Novartis, AstraZeneca, Boehringer Ingelheim, Pfizer, Amgen, and Bristol Myers Squibb.