Study title: Sacubitril/Valsartan Versus Enalapril in Chronic Chagas Cardiomyopathy: Rationale and Design of the PARACHUTE-HF Trial

Presented at: ESC Congress 2025

Link: https://esc365.escardio.org/presentation/312231

Prepared by: Dr. Okan Oğuzhan Ovaz, Dr. Mustafa Yenerçağ

Introduction
Chronic Chagas cardiomyopathy (CCC), caused by Trypanosoma cruzi infection, is characterized by chronic myocarditis involving all cardiac chambers and damage to the conduction system. Compared with other etiologies of heart failure (HF), CCC carries a poorer prognosis. Guideline-directed medical therapy in CCC recommends the use of the same pharmacological agents as for patients with heart failure with reduced ejection fraction (HFrEF) of other causes. The angiotensin-converting enzyme inhibitor (ACEI) enalapril has been reported to exert beneficial effects on left ventricular (LV) diastolic function in CCC-related HF, improving left ventricular ejection fraction (LVEF), enhancing quality of life, and reducing serum B-type natriuretic peptide (BNP) and chemokine levels. In the PARADIGM-HF trial, sacubitril/valsartan significantly reduced the time to cardiovascular death or hospitalization for HF compared with enalapril, irrespective of the underlying etiology, including CCC.

Objective
The PARACHUTE-HF (Prevention And Reduction of Adverse outcomes in Chagasic Heart failUre Trial Evaluation) is an active-controlled, randomized, phase IV trial designed to evaluate whether sacubitril/valsartan 200 mg twice daily, compared with enalapril 10 mg twice daily, in addition to standard HF therapy, reduces the composite of cardiovascular events (cardiovascular death or first hospitalization for HF) and to assess changes in NT-proBNP levels at week 12 in patients with chronic Chagas cardiomyopathy.

Methods
Inclusion criteria: confirmed T. cruzi infection by ≥ 2 different serological tests; LVEF ? 40%; New York Heart Association (NYHA) functional class II–IV HF symptoms; NT-proBNP ≥ 600 pg/mL (or BNP ≥ 150 pg/mL) at baseline, or prior hospitalization for HF with NT-proBNP  ≥ 400 pg/mL (or BNP ≥ 100 pg/mL).
Key exclusion criteria: contraindication, allergy, or intolerance to study medications or their components; systolic blood pressure < 95 mmHg, symptomatic hypotension, or serum potassium > 5.2 mmol/L; prior treatment with sacubitril/valsartan (patients could be included if therapy had been discontinued for > 3 months); advanced hepatic or renal disease; active or symptomatic COVID-19; severe gastrointestinal form of CCC; requirement for continuous intravenous inotropic support or indication for advanced mechanical circulatory support; and other uncontrolled or HF-contributing cardiac conditions.

Participants were randomized in a 1:1 ratio to receive either sacubitril/valsartan (50 or 100 mg twice daily, up-titrated to 200 mg twice daily) or enalapril (2.5 or 5 mg twice daily, up-titrated to 10 mg twice daily). 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 NYHA class II HF, while one-third had class III HF.

The mean baseline NT-proBNP level was approximately 1700 pg/mL, and about 45% of patients had a prior hospitalization for heart failure. Patients were well treated at baseline: 80% were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 90% a beta-blocker, 73% a mineralocorticoid receptor antagonist, and 70% a diuretic.
Investigators performed 212,520 pairwise comparisons by matching participants from each treatment group.

Results
Following pairwise comparisons, sacubitril/valsartan was associated with a 52% higher likelihood of achieving a better primary outcome compared with enalapril (stratified unmatched win ratio 1.52; 95% confidence interval [CI], 1.28–1.82; p<0.001).

Over a median follow-up of 25 months, rates of cardiovascular death (hazard ratio [HR], 0.95; 95% CI, 0.73–1.23) and first HF hospitalization (HR, 0.92; 95% CI, 0.70–1.20) were similar between sacubitril/valsartan and enalapril.

Regarding percentage change in NT-proBNP from baseline to week 12, the log-transformed median change was –30.6% in the sacubitril/valsartan group versus –5.5% in the enalapril group (adjusted geometric mean ratio of change 0.68; 95% CI, 0.62–0.75).

Treatment discontinuation due to adverse events occurred in 6.1% of patients receiving sacubitril/valsartan and in 9.8% of those receiving enalapril.

Conclusions
Patients treated with sacubitril/valsartan demonstrated a significant percentage reduction in NT-proBNP from baseline to week 12. Over a median follow-up of 25 months, rates of cardiovascular death and first HF hospitalization were similar between sacubitril/valsartan and enalapril. The significant difference in the primary outcome was primarily driven by the percentage change in NT-proBNP from baseline to week 12. The safety profiles of the two agents were comparable.

Comment
The PARADIGM-HF trial randomized more than 8,400 patients to treatment, including 113 with Chagas cardiomyopathy, making it the largest study to date in this population. With approximately one-tenth of the sample size, PARACHUTE-HF yielded results largely consistent with those of PARADIGM-HF.
Virtually every guideline-directed medical therapy for heart failure with reduced ejection fraction demonstrates efficacy irrespective of the underlying etiology of heart failure.