A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy

Heart Failure Clinical Trial

Official title:

A Randomized Trial of Carvedilol After Renin-angiotensin System Inhibition in Chronic Chagas Cardiomyopathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01557140
• Other study ID #: Carvedilol in Chagas disease
• Status: Completed
• Phase: Phase 4
• First received: February 21, 2012
• Last updated: August 10, 2015
• Start date: May 2003
• Est. completion date: December 2006

Study information

• Verified date: August 2015
• Source: Federal University of Minas Gerais
• Contact: n/a
• Is FDA regulated: No
• Health authority: Brazil: National Committee of Ethics in Research
• Study type: Interventional

Clinical Trial Summary

Chronic Chagas cardiomyopathy causes substantial morbidity and mortality in Latin America. Whether RAS inhibitors and beta-blockers are safe and beneficial has been challenged because of the lack of formal trials. Hence, the objective of this study was to determine the safety and efficacy of renin-angiotensin system (RAS) inhibitors and beta-blockers in chronic Chagas cardiomyopathy. This way, the investigators conducted a double-blind, placebo-controlled, and randomized trial in 42 patients with Trypanosoma cruzi infection and cardiomyopathy. All patients received enalapril (up-titrated to 20 mg BID) and spironolactone (25 mg QD). Subsequently, the patients were randomly assigned to receive placebo (n = 20) or carvedilol up-titrated to 25 mg BID (n = 19). The primary end points were change in left ventricular ejection fraction (LVEF) after RAS inhibition and that after the addition of carvedilol. The secondary end points were changes in other echocardiographic parameters, Framingham score, quality of life (36-item Short-Form Health Survey), New York Heart Association class, radiographic indices, brain natriuretic peptide levels, and chemokines as well as safety end points.

Description:

Chronic Chagas cardiomyopathy (CCC) is an important cause of heart failure (HF) and sudden death in Latin America.1 According to recent estimates, 13 million people worldwide are infected with Trypanosoma cruzi, of whom 3.0 to 3.3 million are symptomatic.2 The incidence rate is 200000 cases per year. Among those infected, 30% have clinical features of CCC and 15% ultimately develop overt left ventricular (LV) insufficiency—the main prognostic determinant of the disease. In Chagas cardiomyopathy, the hemodynamic and neurohormonal responses do not differ from those in other cardiomyopathies. This common pathophysiology suggests that treatments shown to be effective by classic HF trials should be beneficial in CCC. However, CCC has several specific characteristics, such as early cardiac denervation, frequent ventricular arrhythmias, and several forms as well as grades of conduction disturbances, including sinus bradycardia, complete atrioventricular block, and right bundle-branch block. Morphologically, hypertrophy, dilatation, and severe fibrosis are prominent. In 20% to 40% of cases, an apical ventricular aneurysm is present.1 These peculiarities in combination lead to a high incidence of sudden death (60% of all deaths), cardiac insufficiency, and ventricular remodeling. The responses of patients to the usual drugs prescribed in HF could be different, and this perception has led to the suboptimal dosing or lack of initiation of medical treatments that are of proven efficacy in patients with other etiologies of HF. The underlying problem is that therapies that are effective in patients with HF caused by non-chagasic cardiomyopathies, such as those with renin-angiotensin system inhibitors (RASis) and h-blockers, have yet to be formally tested in CCC. There are few clinical trials and no randomized study on this subject. Consequently, the investigators evaluated the effects of optimizing treatment with enalapril and spironolactone and then undertook a randomized trial of adding a h-blocker in the treatment of patients with CCC.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: December 2006
• Est. primary completion date: March 2004
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Criteria for inclusion were positivity for T cruzi as confirmed by 2 or more serological tests (indirect immunofluorescence, ELISA, and/or indirect hemagglutination) and having cardiomyopathy.

• Cardiomyopathy was present when at least 3 of the following criteria were fulfilled:

• LV enddiastolic diameter (LVDD) N55 mm

• LVDD/body surface area > 2.7cm/m2

• LV ejection fraction (LVEF) < 55%

• QRS interval > 120 ms

• echocardiographic evidence of diffuse or segmental systolic wall motion abnormalities.

Exclusion Criteria:

• Exclusion criteria were being pregnant

• Using any h-blocker

• Having additional comorbidities (eg, hypertension, diabetes mellitus, thyroid dysfunction, chronic obstructive pulmonary disease, asthma, and renal or hepatic failure).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Chagas Cardiomyopathy
• Dilated Cardiomyopathy
• Heart Failure

Intervention

Drug:
• RASi plus carvedilol
Patients were randomly assigned to 2 groups, with 1 group receiving renin-angiotensin system inhibitors (enalapril) plus carvedilol and the other receiving renin-angiotensin system inhibitors (enalapril) plus placebo

Locations

Country	Name	City	State
Brazil	Chagas Disease Outpatient Center of the Federal University of Minas Gerais	Belo Horizonte	Minas Gerais

Sponsors (1)

Lead Sponsor	Collaborator
Federal University of Minas Gerais

Country where clinical trial is conducted

Brazil, 

References & Publications (1)

Botoni FA, Poole-Wilson PA, Ribeiro AL, Okonko DO, Oliveira BM, Pinto AS, Teixeira MM, Teixeira AL Jr, Reis AM, Dantas JB, Ferreira CS, Tavares WC Jr, Rocha MO. A randomized trial of carvedilol after renin-angiotensin system inhibition in chronic Chagas c — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in left ventricular ejection fraction		Baseline, 4 months and 8 months	Yes
Secondary	Changes in Framingham score		Baseline, 4 months and 8 months	No
Secondary	Changes in quality of life (36-item Short-Form Health Survey)		Baseline, 4 months and 8 months	No
Secondary	Changes in New York Heart Association functional class		Baseline, 4 months and 8 months	No
Secondary	Changes in cardiothoracic ratio		Baseline, 4 months and 8 months	No
Secondary	Changes in echocardiographic diastolic function indices		Baseline, 4 months and 8 months	No
Secondary	Changes in brain natriuretic peptide levels		Baseline, 4 months and 8 months	No
Secondary	Changes in chemokines		Baseline, 4 months and 8 months	No
Secondary	Changes in autoantibodies levels		Baseline, 4 months and 8 months	No