The purpose of this study was to evaluate the effect of sacubitril/valsartan 200 mg BID compared with enalapril 10 mg BID, in addition to conventional heart failure (HF) treatment, in improving a hierarchical composite of cardiovascular (CV) events (i.e. CV death or the occurrence of first HF hospitalization) and causing a greater reduction in n terminal prohormone of brain natriuretic peptide (NT-proBNP, at Week 12 from Baseline) in participants with HF with reduced ejection fraction (HFrEF) caused by chronic Chagas' cardiomyopathy (CCC).
This was a multinational, multicenter, parallel-group, prospective, randomized, open-label, with blinded-endpoint adjudication, active-controlled study. The target projected sample size was approximately 900 participants (450 in each arm). It was estimated that approximately 1800 participants would be screened at sites in Latin America, including Argentina, Brazil, Colombia, and Mexico. Participants who met the eligibility requirements were randomly assigned in a 1:1 ratio to receive sacubitril/valsartan (target dose of 200 mg twice daily) or enalapril (target dose of 10 mg twice daily), in addition to their usual therapy, stratified by country, using a central, concealed, web-based, automated randomization system. Both groups entered a titration period of 3 to 6 weeks, aiming to achieve the target dose of sacubitril/valsartan 200 mg twice daily or enalapril 10 mg twice daily. The study follow-up succeeded the titration period and was to last until a total number of 302 events was reached and all randomized participants had a minimum follow-up of 12 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
922
Participants randomized to sacubitril/valsartan who were previously treated with angiotensin-converting enzyme inhibitors (ACEIs) had a 36-hour washout prior to receiving oral treatment with 50, 100, or 200 mg, film-coated tablets.
Oral treatment with 5 or 10 mg tablets.
Novartis Investigative Site
CABA, Buenos Aires, Argentina
Novartis Investigative Site
CABA, Buenos Aires, Argentina
Novartis Investigative Site
Ramos Mejía, Buenos Aires, Argentina
Novartis Investigative Site
San Martín, Buenos Aires, Argentina
Novartis Investigative Site
Temperley, Buenos Aires, Argentina
Hierarchical Composite Endpoint Composed of Time to Cardiovascular (CV) Death, Time to First Heart Failure (HF) Hospitalization, and Relative Change in NT-proBNP From Baseline to Week 12
The primary efficacy endpoint was analyzed using the win ratio approach comparing every participant in the sacubitril/valsartan arm to every participant in the enalapril arm to determine a winner. A winner in the pair-wise comparison had a delayed time to the occurrence of CV death; if time to the occurrence of CV death was censored, a winner had a delayed time to the occurrence of first HF hospitalization event; if the times to both CV events were censored, a winner had a more favorable (less increase or more decrease) change in NT-proBNP between Baseline and Week 12. The estimated win ratio was defined as the total number of winners in the sacubitril/valsartan arm divided by the total number of winners in the enalapril arm. A win ratio \>1 represents a favorable outcome for the study drug being assessed.
Time frame: Total follow-up time up to approximately 36 months
Percentage of Participants Who Died From Cardiovascular Causes
Time frame: Total follow up time up to approximately 36 months
Percentage of Participants With First Hospitalization for Worsening Heart Failure
Time frame: Total follow up time up to approximately 36 months
Change From Baseline to Week 12 in NT-proBNP Levels
Geometric mean factor change was derived from a linear regression model of log(NT-proBNP), adjusted for country and baseline value.
Time frame: Baseline to Week 12
Percentage of Participants With First Hospitalization Due to Heart Failure or Death From Cardiovascular Causes
Time frame: From the date of randomization to the first occurrence (total follow up time up to approximately 36 months)
Percentage of Participants Who Died From Any Cause
Time frame: From date of randomization until the date of death from any cause assessed up to the end of the study, up to approximately 36 months
Number of Participants Who Had Sudden Death or Resuscitated Sudden Cardiac Arrest
Time frame: From date of randomization until the date of the sudden death or resuscitated sudden cardiac arrest assessed up to the end of the study, up to approximately 36 months
Number of Participants Who Had Visits to an Emergency Room Due to Heart Failure (HF) Where Intravenous Therapy Was Required
Time frame: From the date of randomization up to end of study. Total follow up time up to approximately 36 months.
Number of Days Alive and Out of the Hospital
The duration of hospital-free survival within 1 year from randomization was summarized.
Time frame: From the date of randomization up to end of study. Total follow up time up to approximately 36 months.
Number of Hospitalizations Due to Heart Failure (HF) or Death Due to Cardiovascular (CV) Causes (Recurrent Events)
Time frame: From the date of randomization up to end of study. Total follow up time up to approximately 36 months.
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Novartis Investigative Site
Villa María, Córdoba Province, Argentina
Novartis Investigative Site
Salta, Salta Province, Argentina
Novartis Investigative Site
San Miguel de Tucumán, San Miguel de Tucuman, Argentina
Novartis Investigative Site
Rosario, Santa Fe Province, Argentina
Novartis Investigative Site
Rosario, Santa Fe Province, Argentina
...and 69 more locations