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

NCT ID: NCT06431919

Last Updated: 2025-06-08

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 260 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-06-10
• Study Completion Date: 2028-02-29

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).

Detailed Description

Cirrhotic cardiomyopathy (CCM) in chronic liver disease is seen as a blunted contractile responsiveness to stress, and/or altered diastolic relaxation with electrophysiological abnormalities, in absence of known cardiac disease. Cirrhosis induces systemic inflammation, and oxidative stress leading to cardiac structural remodeling, including fibrosis, hypertrophy, and chamber dilation. CCM is associated with risk of LVDD which further lead to hepatorenal syndrome (HRS), septic shock. and peri transplant cardiac complications. Autonomic dysfunction, and neurohormonal imbalances, cardiac arrhythmias, overt heart failure are common features of CCM in advanced liver disease. Efforts to ameliorate the abnormalities associated with CCM are crucial and necessitate a significant evidence-based therapeutic intervention. We have tested the use of carvedilol in this population and found that it causes an improvement in survival.

CCM can be managed by reducing preload (though nitrates), and by ameliorating neurohormonal activation. Lowering the heart rate to 55-65 beats per minute (bpm), as done with β-blockers, is likely to help by improving myocardial oxygen demand and coronary perfusion time with independent effects on portal hypertension, and heart failure. β-blockers may reduce myocardial contractility and patients with cirrhosis have low tolerance to β-blocker dosages required to achieve a THR of 55-65 bpm. Ivabradine is useful in a subset with baseline tachycardia but does not offer survival benefit over carvedilol alone. Therefore, there is a great need to evaluate other agents that can achieve improvement in CCM related complications in cirrhosis.

• Furthermore, β-blockers might diminish myocardial contractility, and patients with cirrhosis may struggle to tolerate β-blocker doses necessary for attaining a target heart rate (THR) of 55-65 bpm. Hence, there's a critical necessity to assess alternative agents capable of ameliorating complications associated with cirrhotic cardiomyopathy (CCM).
• Early interventions to avert cardiovascular morbidity will prove to be cost effective in managing outcome, as they avert high cost of managing the public health burden of all-cause mortality in cirrhosis.
• Cardiovascular complications stand as the primary cause of mortality post-liver transplantation (LT), underscoring the need for thorough evaluation before LT.
• This study will systematically screen participants for coronary artery disease as an integral part of its screening process.
• Statins, particularly simvastatin, exert a favorable impact on vascular reactivity especially in cirrhosis. Simvastatin increases the production of nitric oxide(NO), leading to increased hepatic blood flow and reduced sinusoidal resistance, particularly upon short-term exposure. resistance.
• Simvastatin has an acceptable adverse event profile in decompensated Child B patients. There is no high-quality evidence specifically evaluating the role of simvastatin in cirrhotic cardiomyopathy, although there are data to suggest its efficacy in portal hypertension. The proposed project covers an area of overlap between cardiovascular and liver disease outcomes, which reflect as decompensation events, worsening in liver severity scores and all-cause mortality.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Experimental: Simvastatin + Carvedilol-arm

• 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

Group Type: EXPERIMENTAL

Simvastatin 20mg

Intervention Type: DRUG

Simvastatin fixed dose of 20 mg per day

Carvedilol 3.125 mg

Intervention Type: DRUG

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

Active Comparator: Carvedilol arm

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

Group Type: ACTIVE_COMPARATOR

Carvedilol 3.125 mg

Intervention Type: DRUG

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

Interventions

Simvastatin 20mg

Simvastatin fixed dose of 20 mg per day

Intervention Type: DRUG

Carvedilol 3.125 mg

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.
• Need for medications, metabolized by CYP3A4(such as amlodipine, verapamil, fenofibrate azole antibiotics, protease inhibitors etc.)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Indian Council of Medical Research

OTHER_GOV

Sponsor Role: collaborator

Post Graduate Institute of Medical Education and Research, Chandigarh

OTHER

Sponsor Role: lead

Responsible Party

Madhumita Premkumar

ADDITIONAL PROFESSOR

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Dr Madhumita Premkumar, DM

Role: PRINCIPAL_INVESTIGATOR

Post Graduate Institute of Medical Education and Research, Chandigarh

Locations

PGIMER, Department of Hepatology

Chandigarh, , India

Site Status: RECRUITING

Countries

India

Central Contacts

Dr Madhumita Premkumar, DM

Role: CONTACT

drmadhumitap@gmail.com

7087003409

Facility Contacts

Prerna Sharma, MSc

Role: primary

hepatology.mpk@gmail.com

+911722754777

Other Identifiers

IIRPSG-2024-01-02107

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

PGI/HEP/000214

Identifier Type: -

Identifier Source: org_study_id