Metoprolol Succinate in Cardiac Remodeling Related to Cirrhosis (CARE Cirrhosis)

Effect of Metoprolol Succinate in Cardiac Remodeling Related to Nonalcoholic Cirrhosis. Randomized Study.

Cirrhotic cardiomyopathy is defined as a chronic cardiac dysfunction in patients with cirrhosis. It is suspected that this specific cardiac dysfunction contributes to the onset of complications in liver disease. The purpose of this prospective, randomized trial is to determine whether metoprolol succinate can revert cardiac dysfunction secondary to cirrhosis (cirrhotic cardiomyopathy), and prevent complications (renal dysfunction, mortality). A total of 100 patients with cirrhotic cardiomyopathy will be randomized (Group R) to receive metoprolol succinate or placebo; other 25 patients without cirrhotic cardiomyopathy (Group F) will only be followed up without medication. All patients will be evaluated in the beginning and again after six months. The assessment protocol includes clinical evaluation, electrocardiogram, echocardiogram, laboratory analysis and life quality questionaire. The end points will be cardiac remodeling, electrophysiologic changes, sympathetic activity, laboratory issue changes, renal function, quality of life, and mortality.

Study Overview

• Status: Completed
• Conditions: Cirrhosis; Cardiac Remodeling; Cirrhotic Cardiomyopathy
• Intervention / Treatment: Drug: placebo; Drug: Metoprolol succinate

Detailed Description

Cirrhotic cardiomyopathy (CMC) is defined as a chronic cardiac dysfunction in patients with cirrhosis. Moreover, it is characterized by an abnormal and blunted response to pathological or pharmacological stress in the absence of any other associated cardiac disease. The diagnostic criteria are: baseline increased cardiac output, attenuated myocardial contractile response to stress, diastolic dysfunction, and electrophysiological repolarization abnormalities. It is suspected that cardiac dysfunction in cirrhosis contribute to the onset of complications in liver disease. We will investigate the effect of metoprolol succinate in the reversal of cardiac dysfunction and prevention of complications of cirrhosis in patients with cirrhotic cardiomyopathy. Furthermore, we want to study the influence of presence of CMC in the evolution of cirrhotic patients. The study will be prospective, randomized, double-blind, and placebo-controlled. The sample consists of 125 patients aged between 18 and 60 years old diagnosed with severe liver cirrhosis (Child B or C or MELD score above 10) with cirrhotic cardiomyopathy or not. Of these, 100 patients with cirrhotic cardiomyopathy will be randomized into two groups: group R1 (metoprolol succinate) and group R2 (placebo). Group F will consist of cirrhotic patients without cardiomyopathy and will not receive medication. Patients will be evaluated by clinical examination, resting electrocardiogram, 24-hour Holter, stress echocardiography and laboratory (brain natriuretic peptide (BNP), catecholamines, plasma renin activity, and troponin) at inclusion and after six months. The end points are: 1) Reversal of cardiac dysfunction in patients with cirrhotic cardiomyopathy, 2) Development of hepatorenal syndrome, 3) Reversal of the electrophysiologic abnormalities, 4)Changes in laboratory tests, and 5) Mortality.

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo, Brazil, 05403000
    • University of Sao Paulo School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• more than 18 years old.
• must have signed the written informed consent.
• nonalcoholic cirrhosis.

Exclusion Criteria:

• Betablockers intolerance;
• Diagnosis of other cardiomyopathy
• Chronicle renal disease (Creatinine > 2.5)
• Heavy alcohol intake history
• Presence of other disease with possible cardiac implication (infiltrative or storage disease)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: placebo
Active Comparator: Metoprolol succinate	Drug: Metoprolol succinate; Other Names: Selozok
No Intervention: Follow up; Group without cirrhotic cardiomyopathy, only follow up without randomization.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of systolic function	Systolic functional reserve is measured by aortic velocity time integral in echocardiographic at rest and stress with dobutamine.	six months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in left ventricular diastolic function		six months
Renal function		From randomization until six months
Serum level of BNP, catecholamines, plasmatic renin activity		Six months
Mortality		From randomization until six months of follow up
Quality of life		Six months
Electrophysiologic modifications	QT prolongation R-R variability	Six months

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Investigators: Principal Investigator: Fernando Bacal, MD, PhD, University of Sao Paulo School of Medicine

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: August 28, 2012
• First Submitted That Met QC Criteria: August 29, 2012
• First Posted (Estimate): August 30, 2012

Study Record Updates

• Last Update Posted (Estimate): September 11, 2014
• Last Update Submitted That Met QC Criteria: September 9, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Cirrhosis; cardiomyopathy; cardiac remodeling; cirrhotic cardiomyopathy; metoprolol succinate; betablockers
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Liver Diseases; Fibrosis; Liver Cirrhosis; Cardiomyopathies; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Metoprolol
• Other Study ID Numbers: 0010/11