A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Antonio Luiz Pinho Ribeiro, Federal University of Minas Gerais
ClinicalTrials.gov Identifier:
NCT01557140
First received: February 21, 2012
Last updated: March 16, 2012
Last verified: March 2012
  Purpose

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.


Condition Intervention Phase
Chagas Cardiomyopathy
Heart Failure
Dilated Cardiomyopathy
Drug: RASi plus carvedilol
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Trial of Carvedilol After Renin-angiotensin System Inhibition in Chronic Chagas Cardiomyopathy

Resource links provided by NLM:


Further study details as provided by Federal University of Minas Gerais:

Primary Outcome Measures:
  • Changes in left ventricular ejection fraction [ Time Frame: Baseline, 4 months and 8 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Changes in Framingham score [ Time Frame: Baseline, 4 months and 8 months ] [ Designated as safety issue: No ]
  • Changes in quality of life (36-item Short-Form Health Survey) [ Time Frame: Baseline, 4 months and 8 months ] [ Designated as safety issue: No ]
  • Changes in New York Heart Association functional class [ Time Frame: Baseline, 4 months and 8 months ] [ Designated as safety issue: No ]
  • Changes in cardiothoracic ratio [ Time Frame: Baseline, 4 months and 8 months ] [ Designated as safety issue: No ]
  • Changes in echocardiographic diastolic function indices [ Time Frame: Baseline, 4 months and 8 months ] [ Designated as safety issue: No ]
  • Changes in brain natriuretic peptide levels [ Time Frame: Baseline, 4 months and 8 months ] [ Designated as safety issue: No ]
  • Changes in chemokines [ Time Frame: Baseline, 4 months and 8 months ] [ Designated as safety issue: No ]
  • Changes in autoantibodies levels [ Time Frame: Baseline, 4 months and 8 months ] [ Designated as safety issue: No ]

Enrollment: 42
Study Start Date: May 2003
Study Completion Date: December 2006
Primary Completion Date: March 2004 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: RASi plus placebo
RAS inhibition was optimized and after patients were randomly assigned to receive placebo
No Intervention: RASi plus carvedilol
RAS inhibition was optimized and after patients were randomly assigned to receive carvedilol
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
Other Names:
  • Randomized
  • Double blind
  • Controlled
  • Trial

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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).
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01557140

Locations
Brazil
Chagas Disease Outpatient Center of the Federal University of Minas Gerais
Belo Horizonte, Minas Gerais, Brazil
Sponsors and Collaborators
Federal University of Minas Gerais
Investigators
Principal Investigator: Fernando A Botoni, MD, PhD Federal University of Minas Gerais
  More Information

Publications:
Responsible Party: Antonio Luiz Pinho Ribeiro, Director-General, Hospital das Clínicas, UFMG, Federal University of Minas Gerais
ClinicalTrials.gov Identifier: NCT01557140     History of Changes
Other Study ID Numbers: Carvedilol in Chagas disease
Study First Received: February 21, 2012
Last Updated: March 16, 2012
Health Authority: Brazil: National Committee of Ethics in Research

Keywords provided by Federal University of Minas Gerais:
Chagas cardiomyopathy,
Renin-angiotensin system,
Beta-blockers,
Enalapril,
Carvedilol,
Renin-angiotensin system inhibitors,
Brain natriuretic peptide level,
Left ventricular ejection fraction,
Chemokines

Additional relevant MeSH terms:
Cardiomyopathy, Dilated
Chagas Cardiomyopathy
Heart Failure
Cardiomyopathies
Cardiomegaly
Heart Diseases
Cardiovascular Diseases
Chagas Disease
Trypanosomiasis
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Natriuretic Peptide, Brain
Carvedilol
Natriuretic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists

ClinicalTrials.gov processed this record on July 24, 2014