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

Acute Kidney Injury Clinical Trial

— CIRROSTAT  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06431919
• Other study ID #: PGI/HEP/000214
• Status: Not yet recruiting
• Phase: N/A
• Start date: August 2024
• Est. completion date: August 2027

Study information

• Verified date: May 2024
• Source: Post Graduate Institute of Medical Education and Research, Chandigarh
• Contact: Dr Madhumita Premkumar, DM
• Phone: 7087003409
• Email: drmadhumitap[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 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:

We 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).

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(1, 6). 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)(7), septic shock. (8) and peri transplant cardiac complications.(9) 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(10, 11) 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 (8).

• Kaplan et al showed extended exposure to simvastatin (1 month regimen, comprising 20 mg/day for the initial 15 days followed by 40 mg/day for the subsequent 15 days) resulted in a significant decrease in hepatic venous portal pressure as compared to control placebo. Additionally, this prolonged regimen exhibited improvements in hepatocyte metabolic function.(9).

• Simvastatin has an acceptable adverse event profile in decompensated Child B patients (10, 11). 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 260
• Est. completion date: August 2027
• Est. primary completion date: August 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.)

Related Conditions & MeSH terms

• Acute Kidney Injury
• Cardiomyopathies
• Cirrhosis, Liver
• Cirrhotic Cardiomyopathy
• Decompensated Cirrhosis
• Fibrosis
• Left Ventricular Diastolic Dysfunction
• Liver Cirrhosis
• Liver Diseases
• Ventricular Dysfunction, Left

Intervention

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

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Post Graduate Institute of Medical Education and Research, Chandigarh	Indian Council of Medical Research

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	All-cause Mortality		From enrollment until 1 year of follow up
Secondary	New decompensation event		1 Year
Secondary	Improvement in CCM parameters (left ventricular diastolic function) in either arm based on Echocardiography and Cardiac Imaging		1 Year
Secondary	Episodes warranting hospitalization		1 Year
Secondary	Serum level of BNP and other cardiac and inflammatory biomarkers	ELISA or autoanalyzer will be performed for qunatification	1 Year