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

Carvedilol + Simvastatin vs. Carvedilol Alone for Chronic Liver Disease and Cirrhotic Cardiomyopathy and Its Impact on Hepatic Decompensation and Survival; a Double-blind Randomized Controlled Trial

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).

Study Overview

• Status: Recruiting
• Conditions: Decompensated Cirrhosis; Acute Kidney Injury; Cirrhosis, Liver; Left Ventricular Diastolic Dysfunction; Cirrhotic Cardiomyopathy
• Intervention / Treatment: Drug: Simvastatin 20mg; Drug: Carvedilol 3.125 mg

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.

• Study Type: Interventional
• Enrollment (Estimated): 260
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dr Madhumita Premkumar, DM; Phone Number: 7087003409; Email: drmadhumitap@gmail.com

Study Locations

• India
  • Chandigarh, India, 160012
    • Recruiting
    • PGIMER, Department of Hepatology
    • Contact: Prerna Sharma, MSc; Phone Number: +911722754777; Email: hepatology.mpk@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: Simvastatin 20mg; Simvastatin fixed dose of 20 mg per day; Drug: Carvedilol 3.125 mg; Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate
Active Comparator: 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	Drug: Carvedilol 3.125 mg; Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality		From enrollment until 1 year of follow up
Improvement in CCM parameters (left ventricular diastolic function) in either arm based on Echocardiography and Cardiac Imaging		1 Year
Serum level of BNP and other cardiac and inflammatory biomarkers	ELISA or autoanalyzer will be performed for qunatification	1 Year
Any New decompensation event	New decompensation events are defined as decompensation event( ascites, hepatic encephalopathy, variceal bleeding) in a previously compensated patient with cirrhosis or further decompensation when a new event [recurrence of ascites, hepatorenal syndrome-acute kidney injury (HRS-AKI), hepatic encephalopathy (HE), or acute variceal bleeding (AVB), spontaneous bacterial peritonitis (SBP)] occurs in a patient with previously decompensated disease	1 Year
Episodes warranting hospitalization	Number of hospital admissions on follow up.	1 Year

Collaborators and Investigators

• Sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh
• Collaborators: Indian Council of Medical Research
• Investigators: Principal Investigator: Dr Madhumita Premkumar, DM, PGIMER

Study record dates

Study Major Dates

• Study Start (Estimated): June 10, 2025
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): February 1, 2028

Study Registration Dates

• First Submitted: May 22, 2024
• First Submitted That Met QC Criteria: May 22, 2024
• First Posted (Actual): May 29, 2024

Study Record Updates

• Last Update Posted (Actual): June 8, 2025
• Last Update Submitted That Met QC Criteria: June 5, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Acute kidney injury; Decompensated Cirrhosis; Cirrhotic Cardiomyopathy; Left ventricular diastolic dysfunction
• Additional Relevant MeSH Terms: Urogenital Diseases; Cardiovascular Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Heart Diseases; Digestive System Diseases; Liver Diseases; Renal Insufficiency; Ventricular Dysfunction; Acute Kidney Injury; Fibrosis; Ventricular Dysfunction, Left; Cardiomyopathies; Liver Cirrhosis; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Neurotransmitter Agents; Membrane Transport Modulators; Antioxidants; Protective Agents; Adrenergic Agents; Calcium Channel Blockers; Vasodilator Agents; Antihypertensive Agents; Adrenergic beta-Antagonists; Adrenergic Antagonists; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Carvedilol; Simvastatin
• Other Study ID Numbers: PGI/HEP/000214; IIRPSG-2024-01-02107 (Other Grant/Funding Number: Indian Council of Medical Research)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No