Carvedilol + Simvastatin vs. Carvedilol Alone for Cirrhosis and Cirrhotic Cardiomyopathy and Impact on Hepatic Decompensation and Survival

NCT06431919 | Recruiting DMC

• 2 other identifiers: PGI/HEP/000214IIRPSG-2024-01-02107
• Study Type: interventional
• Target: 260
• Locations: 1 country
• Sites: 1

Brief Summary

Cirrhosis and portal hypertension are associated with a hyperdynamic circulation and decompensation events, including development of ascites, variceal bleeding, acute kidney injury, and susceptibility to infections. Rationale: Cirrhosis and portal hypertension are associated with a hyperdynamic circulation and decompensation events, including ascites, variceal bleeding, acute kidney injury, and susceptibility to infections. CCM, present in 30-70% of patients, is characterized by structural and functional abnormalities in the heart, and is associated with progression of cirrhosis, impaired quality of life and poor survival. Statins play a crucial role in reducing proatherogenic LDL cholesterol levels, making them a cornerstone in managing diabetes and cardiovascular diseases (CVDs) with the aim of decreasing or reversing atherosclerosis. This trial aims to evaluate the impact and safety of simvastatin in cirrhotic cardiomyopathy. Novelty: Simvastatin might be of special value in diastolic dysfunction through its hemodynamic and functional effects on LV remodeling and improve portal hemodynamics through the pleotropic effects of lipophilic statins. Objectives: The primary objective is to assess the combined effects of carvedilol and simvastatin in managing CCM vs carvedilol alone for a composite outcome to prevent decompensation and reduce all-cause mortality. We will comprehensively evaluate cardiac function, decompensation events and survival based on impact of simvastatin over the standard betablocker carvedilol. Methods: This is a double-blinded randomized placebo-controlled trial involving patients diagnosed with CCM. Clinical data, including cardiac imaging, cardiac biomarkers, and survival outcomes, will be assessed for either group. Expected Outcome: The investigators anticipate that the synergistic use of simvastatin and carvedilol will effectively reduce portal pressure, improve portal haemodynamic, and enhance cardiac remodelling. Successful reversal of LVDD can potentially prevent clinical events such as ascites, encephalopathy, and acute kidney injury (AKI).

Conditions

Decompensated Cirrhosis; Cirrhotic Cardiomyopathy; Cirrhosis, Liver; Left Ventricular Diastolic Dysfunction; Acute Kidney Injury

Keywords

Decompensated Cirrhosis; Cirrhotic Cardiomyopathy; Left ventricular diastolic dysfunction; Acute kidney injury

Outcome Measures

Primary Outcomes (1)

• Time to acute decompensation event

  The primary outcome measure is defined as a composite end point of acute decompensation event (acute variceal bleeding, new ascites or recurrence of previously controlled ascites, episode of hepatic encephalopathy or acute kidney injury) OR all-cause death in patients with cirrhosis and cirrhotic cardiomyopathy

  1 Year

Secondary Outcomes (5)

• All-cause Mortality

  From enrollment until 1 year of follow up

• Any New decompensation event

  1 Year

• Improvement in CCM parameters (left ventricular diastolic function) in either arm based on Echocardiography and Cardiac Imaging

  1 Year

• Episodes warranting hospitalization

  1 Year

• Serum level of BNP and other cardiac and inflammatory biomarkers

  1 Year

Study Arms (2)

Experimental: Simvastatin + Carvedilol-arm

EXPERIMENTAL

* Simvastatin fixed dose of 20 mg per day * Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate * Standard Medical Therapy

Drug: Simvastatin 20mg; Drug: Carvedilol 3.125 mg

Active Comparator: Carvedilol arm

ACTIVE COMPARATOR

* Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate * Standard Medical Therapy

Drug: Carvedilol 3.125 mg

Interventions

Simvastatin 20mg DRUG

Simvastatin fixed dose of 20 mg per day

Experimental: Simvastatin + Carvedilol-arm

Carvedilol 3.125 mg DRUG

Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate

Active Comparator: Carvedilol arm; Experimental: Simvastatin + Carvedilol-arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age range of 18-65 years
• Compensated cirrhosis, as diagnosed by histology or clinical, laboratory and USG findings,
• CCM (with EF\>50%) on 2D echocardiography with TDI
• Written informed consent.

You may not qualify if:

• Age \>65 years
• Serum Creatinine\>2 mg/dl
• Patient previously treated with statin (one month before the study)
• Contraindications to statins
• Advanced Cirrhosis (CTP score\>9)
• Coronary artery disease
• Sick sinus syndrome/ Pacemaker, valvular heart disease
• Cardiac rhythm disorder, Peripartum cardiomyopathy
• Portopulmonary hypertension/ hepatopulmonary syndrome
• Transjugular intrahepatic portosystemic shunt (TIPS) insertion
• Hepatocellular carcinoma
• Pregnancy or lactation
• Patients with HIV or retroviral therapy
• Anemia Hb \< 8gm/dl in females, and \< 9 gm/dl in males
• Acute variceal bleeding in last 6 months.

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead
• Indian Council of Medical Research: collaborator

Study Sites (1)

PGIMER, Department of Hepatology

Chandigarh, 160012, India

RECRUITING

MeSH Terms

Conditions

Liver Cirrhosis; Ventricular Dysfunction, Left; Acute Kidney Injury

Interventions

Simvastatin; Carvedilol

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Ventricular Dysfunction; Heart Diseases; Cardiovascular Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring

Study Officials

• Dr Madhumita Premkumar, DM

  Post Graduate Institute of Medical Education and Research, Chandigarh

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dr Madhumita Premkumar, DM

CONTACT

7087003409; drmadhumitap@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind randomized controlled trial
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: ADDITIONAL PROFESSOR

Study Record Dates

• First Submitted: May 22, 2024
• First Posted: May 29, 2024
• Study Start: June 10, 2025
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): February 1, 2028
• Last Updated: June 8, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)